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Drugs affecting cardiovascular function - Pharmacology for Medical Graduates, 4th Updated Edition

Shanbhag, Tara V, MD; Shenoy, Smita, MD;

Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 3, 98-150

Antihypertensive drugs PH1.26, PH1.27

Hypertension is a common cardiovascular disease affecting worldwide population. A persistent and sustained high blood pressure has damaging effects on the heart, brain, kidneys and eyes. Hypertension could be:

  • 1.

    Primary or essential hypertension: It is the most common type. There is no specific underlying cause.

  • 2.

    Secondary hypertension: It can be due to renal, vascular, endocrine disorders, etc.

Blood pressure

Various guidelines for hypertension are available (JNC 8 – 2014, American College of Cardiology [ACC] and American Heart Association [AHA] Guidelines, 2017). A systolic blood pressure of <120 mm Hg and diastolic pressure <80 mm Hg is considered as normal BP. The risk of cardiovascular disease (CVD) increases with increase in blood pressure. This risk is taken into consideration while determining the target BP to be achieved following initiation of treatment with antihypertensive drugs.

  • ■

    Systolic blood pressure (SBP): It is the maximum pressure recorded during ventricular systole.

  • ■

    Diastolic blood pressure (DBP): It is the minimum pressure recorded during ventricular diastole.

  • ■

    Pulse pressure (PP): It is the difference between SBP and DBP ( PP = SBP – DBP).

  • ■

    Mean arterial pressure: DBP + 1/3 PP.

Classification of antihypertensive drugs ( fig. 3.1 )

  • 1.

    Angiotensin converting enzyme (ACE) inhibitors: Captopril, enalapril, lisinopril, perindopril, ramipril, benazepril, fosinopril.

    Fig. 3.1
    Sites of action of major groups of antihypertensive drugs. VMC, vasomotor centre (medulla); ACE, angiotensin converting enzyme; AT 1 , angiotensin receptor.
    (Source: Adapted from Bertram G. Katzung, Susan B. Masters., and Anthony J. Trevor, Editors: Basic and Clinical Pharmacology, 12e, McGraw Hill, 2012.)

  • 2.

    Angiotensin receptor blockers (ARBs): Losartan, candesartan, irbesartan, valsartan, telmisartan, olmesartan, eprosartan.

  • 3.

    Direct renin inhibitor: Aliskiren.

  • 4.

    Calcium channel blockers (CCBs): Diltiazem, verapamil, nifedipine, amlodipine, cilnidipine, nicardipine, benidipine, isradipine, felodipine, lacidipine, lercanidipine.

  • 5.

    Diuretics

    • (a)

      Thiazides and related agents: Hydrochlorothiazide, chlorthalidone, indapamide.

    • (b)

      Loop diuretics: Furosemide, bumetanide, torsemide.

    • (c)

      Potassium-sparing diuretics: Amiloride, triamterene, spironolactone, eplerenone.

  • 6.

    Sympatholytic agents

    • (a)

      Centrally acting sympatholytics: Clonidine, α-methyldopa.

    • (b)

      β-Adrenergic blockers: Atenolol, metoprolol, esmolol, betaxolol, propranolol, timolol.

    • (c)

      β-Adrenergic blockers with additional α- blocking activity: Labetalol, carvedilol, nebivolol.

    • (d)

      α-Adrenergic blockers:

      • ■

        Selective : Prazosin, terazosin, doxazosin.

      • ■

        Nonselective : Phenoxybenzamine, phentolamine.

  • 7.

    Vasodilators

    • (a)

      Arteriolar dilators: Hydralazine, minoxidil, diazoxide, fenoldopam.

    • (b)

      Primarily venodilator: Nitroglycerin.

    • (c)

      Arteriolar and venodilator: Sodium nitroprusside.

Angiotensin converting enzyme inhibitors ( fig. 3.2 ) PH1.26

ACE inhibitors are frequently used as first-line antihypertensive drugs.

Fig. 3.2
Site of action of ACE inhibitors. Effects of angiotensin II are prevented by ACE inhibitors.
( Source: Adapted from Bertram G. Katzung, Susan B. Masters., and Anthony J. Trevor, Editors: Basic and Clinical Pharmacology, 12e, McGraw Hill, 2012.)

Mechanism of action.

ACE inhibitors

  • 1.

    Inhibit the generation of angiotensin II resulting in:

    • ■

      Dilatation of arterioles →⇩ peripheral vascular resistance (PVR) →⇩ BP.

    • ■

      Decrease in aldosterone production → decrease in Na + and H 2 O retention →⇩ BP.

    • ■

      Decrease in sympathetic nervous system activity.

  • 2.

    Inhibit degradation of bradykinin (potent vasodilator) by ACE.

  • 3.

    Stimulate synthesis of vasodilating prostaglandins through bradykinin.

All these actions contribute to their antihypertensive effect . They also reverse ventricular and vascular hypertrophy

Pharmacokinetics.

ACE inhibitors are usually given orally. In hypertensive emergency, enalaprilat can be given intravenously. Food reduces the absorption of captopril; hence, it should be given 1 hour before meals. ACE inhibitors poorly cross the blood–brain barrier (BBB), are metabolized in the liver and excreted in urine ( Table 3.1 ).

Table 3.1 ■
Pharmacokinetic features of ACE inhibitors
Features Drug
Captopril Enalapril Lisinopril Perindopril Ramipril Fosinopril Benazepril Trandolapril Quinapril
Active Prodrug Active Prodrug Prodrug Prodrug Prodrug Prodrug Prodrug
Absorption Well absorbed; food reduces absorption, hence given 1 hour before food Rapidly absorbed but undergoes extensive first-pass metabolism; food does not reduce its absorption Slowly and incompletely absorbed; food does not affect its absorption Poorly absorbed; food does not affect its absorption Rapidly absorbed Poorly absorbed; rate of absorption is affected by food Poorly absorbed Moderately absorbed; food does not affect its absorption Rapidly absorbed
Duration of action 8–12 h 24 h >24 h >24 h >24 h 24 h 24 h 24 h 24 h
Route of excretion Kidney Kidney Kidney Kidney Kidney Kidney and bile Kidney Kidney and stools Kidney and stools

Adverse effects *

* Mnemonic for adverse effects of ACE inhibitors: ‘ CAPTOPRIL ’.

and contraindications

  • 1.

    C ough (dry cough): Bradykinin is metabolized by ACE. Inhibition of ACE results in increased bradykinin levels in the lungs and causes cough. Appearance of intractable cough is an indication to stop the drug. It subsides following discontinuation of the drug.

  • 2.

    A ngioedema: Swelling in the nose, lips, mouth, throat, larynx and glottis. There can be airway obstruction – patient’s airway should be protected. If required, adrenaline, glucocorticoids and antihistamines should be administered.

  • 3.

    P roteinuria can occur rarely. The drug should be discontinued.

  • 4.

    T eratogenic effect (growth retardation, foetal hypotension, renal failure and neonatal death) – hence contraindicated in pregnancy.

  • 5.

    Hyp O tension may occur following the first dose of ACE inhibitor – this can be marked in patients who are volume depleted or have congestive heart failure (CHF).

  • 6.

    Neutro P enia is rare.

  • 7.

    R ashes.

  • 8.

    I tching: Discontinuation of the drug is not required.

  • 9.

    L oss of taste sensation (dysgeusia).

  • 10.

    Hyperkalaemia: In patients receiving ACE inhibitors, hyperkalaemia may occur in the presence of renal insufficiency or when they are combined with potassium-sparing diuretics.

ACE inhibitors are contraindicated in patients with bilateral renal artery stenosis as acute renal failure can be precipitated. When renal perfusion pressure is low, angiotensin II maintains glomerular filtration rate (GFR) by constriction of efferent arteriole. This is blocked by ACE inhibitor.

ACE inhibitors are also contraindicated in patients with single kidney with renal artery stenosis as they can precipitate renal failure.

Drug interactions

  • 1.

    ACE inhibitors × potassium-sparing diuretics: Simultaneous administration of these drugs can cause dangerous hyperkalaemia.

  • 2.

    ACE inhibitors × lithium: ACE inhibitors retard renal elimination of lithium and potentiate its toxicity.

  • 3.

    ACE inhibitors × NSAIDs: NSAIDs by inhibiting PG synthesis promote Na + and water retention on chronic use. Thus, they decrease antihypertensive effect of ACE inhibitors.

  • 4.

    Thiazides × ACE inhibitors: Diuretics increase the antihypertensive effect of ACE inhibitors by promoting the loss of Na + and water. Serum potassium levels are maintained by the combination.

Therapeutic uses of ACE inhibitors

  • 1.

    Hypertension: (Mode of action: see p. 100) ACE inhibitors are used in all grades of hypertension. They decrease cardiovascular and cerebrovascular morbidity and mortality (fatal and nonfatal myocardial infarction (MI), fatal and nonfatal stroke, CHF and sudden death). They do not cause electrolyte disturbances, hyperuricaemia, alterations in lipid levels and sexual dysfunction. They are preferred in hypertensive patients with diabetes because they delay or prevent progression of renal complications. They are also preferred in hypertensives with coexisting CHF, left ventricular (LV) hypertrophy and peripheral vascular disease.

  • 2.

    Acute MI: ACE inhibitors should be started within 24 hours in patients with MI. They have shown both short-term and long-term improvement in survival and decrease in reinfarction.

  • 3.

    CHF: ACE inhibitors should be prescribed to all patients with impaired LV function (for explanation see p. 125).

  • 4.

    Diabetic nephropathy: ACE inhibitors and angiotensin II receptor blockers (ARBs) are the preferred drugs in diabetic nephropathy in hypertensive as well as normotensive patients.

    • They decrease systemic blood pressure and dilate renal efferent arteriole →↓ intraglomerular pressure; inhibit angiotensin II-mediated mesangial cell growth. They decrease microalbuminuria.

  • 5.

    Scleroderma renal crisis: ACE inhibitors prevent the effects of angiotensin II in the renal artery; thus, they are effective in the treatment of scleroderma renal crisis. Survival rate is increased.

Angiotensin receptor blockers or angiotensin receptor antagonists

They are losartan, irbesartan, candesartan, olmesartan, valsartan and telmisartan; administered orally. The two types of angiotensin II receptors are AT 1 and AT 2 . Most of the effects of angiotensin II are mediated by AT 1 receptors. They are vasoconstriction, aldosterone secretion and the release of noradrenaline from sympathetic nerve endings. The role of AT 2 receptors is not known.

Angiotensin receptor blockers competitively inhibit the binding of angiotensin II to AT 1 -receptor subtype and block its effects. Angiotensin receptor blockers produce effects similar to those of ACE inhibitors. Angiotensin receptor blockers do not affect bradykinin degradation.

Adverse effects.

Angiotensin receptor blockers are better tolerated as compared to ACE inhibitors. They cause headache, hypotension, weakness, rashes, nausea, vomiting and teratogenic effects. They may cause hyperkalaemia in patients with renal failure or in patients on K + -sparing diuretics. They are less likely to produce cough or angioedema than ACE inhibitors.

Uses.

Angiotensin receptor blockers are used in hypertension, congestive cardiac failure (CCF), MI and diabetic nephropathy. The antihypertensive efficacy of ARBs is comparable with that of ACE inhibitors. Like ACE inhibitors, ARBs prevent/delay the development of renal complications in diabetes patients. Angiotensin receptor blockers are mainly indicated in patients who develop cough with ACE inhibitors.

In CCF and MI, ARBs are used in patients who are intolerant to ACE inhibitors.

Direct renin inhibitor: Aliskiren

Aliskiren, by inhibiting renin, decreases levels of angiotensin I and angiotensin II. It is useful in hypertension in combination with diuretics, ACE inhibitors or ARBs (increased antihypertensive efficacy). It is administered orally. Adverse effects include diarrhoea, abdominal pain, headache and angioedema.

Diuretics

Thiazides and related drugs are widely used drugs for uncomplicated hypertension. Chlorothiazide, hydrochlorothiazide and chlorthalidone are the commonly used thiazides.

Thiazide diuretics.

These are used in uncomplicated mild to moderate hypertension and have a long duration of action. They should be administered in a low dose, i.e. 12.5 mg of chlorthalidone or hydrochlorothiazide. If the antihypertensive response is not adequate, the dose can be increased up to 25 mg/day. Beyond this dose, thiazides are not safe. Potassium-sparing diuretics are usually given with thiazides to counteract K + loss and increase antihypertensive efficacy. Use of ACE inhibitors with thiazides decreases K + loss by thiazides and enhances antihypertensive effect.

Mechanism of action of thiazides

Adverse effects.

They are hypokalaemia, hyperglycaemia, hyperuricaemia, hyperlipidaemia, hypercalcaemia, impotence and decreased libido.

Advantages of thiazides

  • ■

    Have long duration of action (administered once daily).

  • ■

    Are cheap.

  • ■

    Are well tolerated by elderly patients.

  • ■

    Decrease the incidence of fracture in elderly patients by reducing urinary Ca 2+ excretion.

  • ■

    Have synergistic effect when used in combination with other antihypertensive drugs.

Chlorthalidone is a frequently used thiazide-like diuretic in hypertension as it has a long duration of action. Indapamide and metolazone are more potent, longer acting and produce fewer adverse effects than thiazides.

Loop diuretics.

These drugs have short duration of action, so a sustained Na + deficit is not maintained; therefore, they are not used routinely in hypertension except in the presence of renal or cardiac failure.

Calcium channel blockers

Verapamil, diltiazem and dihydropyridines (DHPs; nifedipine, amlodipine, cilnidipine, felodipine, nicardipine, isradipine, etc.) are useful in all grades of hypertension.

The antihypertensive effect is mainly due to peripheral vasodilatation. DHPs are more likely to cause headache, flushing, ankle oedema, palpitation and reflex tachycardia. The use of sustained-release preparations reduces the incidence of side effects. β-Blockers can be used with nifedipine to counteract the reflex tachycardia. Reflex tachycardia is minimal or absent with verapamil and diltiazem because of their greater cardiac depressant effect. Verapamil and diltiazem should be avoided in patients with cardiac dysfunction because of their cardiac depressant effect. CCBs are particularly useful in elderly patients, in patients with angina, asthma, peripheral vascular disease, migraine, hyperlipidaemia, diabetes and renal dysfunction. They are used as monotherapy or in combination with other antihypertensives. They decrease albuminuria and also slow the progression of nephropathy in diabetes patients. Intravenous clevidipine is useful in treating severe hypertension.

Sympatholytics

β-adrenergic blockers.

β-Blockers are effective in all grades of hypertension.

  • ■

    Selective β-blockers (block only β 1 ), e.g. atenolol, metoprolol, esmolol and betaxolol

  • ■

    Nonselective β-blockers (block both β 1 and β 2 ), e.g. propranolol and timolol

During initial therapy with β-blockers, cardiac output (CO) decreases but peripheral vascular resistance may increase. On chronic therapy, peripheral vascular resistance gradually decreases because of sustained reduction in CO – BP falls. Other mechanisms of antihypertensive effect are shown in Fig. 3.3 . β-Blockers are mainly useful in:

  • ■

    Young hypertensives with high renin levels.

  • ■

    Patients with associated conditions, such as angina, post-MI, migraine and psychosomatic disorders.

  • ■

    Patients receiving vasodilators to counteract reflex tachycardia.

Fig. 3.3
Mechanism of antihypertensive effect of β-blockers.

β-Blockers may precipitate CCF and bronchospasm in susceptible individuals. They can cause sexual dysfunction in males and nightmares. They must be used with caution in diabetes patients receiving hypoglycaemic drugs. Sudden stoppage of β-blockers, after prolonged therapy, can produce withdrawal syndrome due to sympathetic overactivity ( Table 1.6 ).

Centrally acting sympatholytics

Clonidine.

Clonidine is a centrally acting antihypertensive drug.

Mechanism of action ( fig. 3.4 ).

Clonidine is effective orally; it is highly lipid soluble and rapidly crosses the BBB. It has a short duration of action, requires twice a day administration. Transdermal patch of clonidine controls BP for a week.

Fig. 3.4
Mechanism of action of clonidine.

Adverse effects.

Dryness of mouth and eyes, sedation, depression, bradycardia, impotence, nausea, dizziness, parotid gland swelling and pain are the adverse effects of clonidine. Postural hypotension may occur.

Sudden stoppage of clonidine after prolonged use may cause withdrawal syndrome – headache, nervousness, tachycardia, sweating, tremors, palpitation and rebound hypertension. This is due to:

  • ■

    Supersensitivity of α-receptors.

  • ■

    Precipitous release of large amount of stored catecholamines.

This is treated with intravenous sodium nitroprusside or labetalol.

Uses.

Clonidine is useful:

  • 1.

    In hypertension.

  • 2.

    To treat withdrawal symptoms in opioid and alcohol addicts and smoking cessation.

  • 3.

    As preanaesthetic agent.

  • 4.

    As antidiarrhoeal in diabetic neuropathy.

  • 5.

    To reduce postmenopausal hot flushes.

  • 6.

    For prophylaxis of migraine.

α-methyldopa.

It is a centrally acting sympatholytic agent.

Mechanism of action

α-Methyldopa, a prodrug, which enters the adrenergic neuron, is converted into an active form and stored in the neurons. α-Methylnoradrenaline is a false transmitter that is released during nerve stimulation instead of noradrenaline. α-Methylnoradrenaline acts by stimulating α 2 -receptors in vasomotor centre.

Adverse effects.

These include nasal stuffiness, headache, sedation, mental depression, dryness of mouth, bradycardia, impotence, gynaecomastia, hepatitis and rarely haemolytic anaemia.

Clonidine and α-methyldopa are usually employed as the second- or third-line agents in hypertension because of high incidence of side effects. α-Methyldopa is one of the preferred antihypertensive drugs during pregnancy.

α-adrenergic blockers

Nonselective α-blockers are not preferred for essential hypertension. They are useful to treat hypertension in special conditions like pheochromocytoma, clonidine withdrawal and cheese reaction.

Pharmacokinetics, adverse effects and uses of α-blockers are discussed on p. 89–91.

Selective α 1 - blockers: Prazosin causes first-dose phenomenon – postural hypotension that occurs after the first dose. Therefore, the initial dose should be small (1 mg) and usually given at bedtime so that the patient remains in bed for several hours, hence reduces the risk of fainting attacks.

Terazosin and doxazosin are longer acting than prazosin, given once daily in the treatment of hypertension.

Vasodilators

Minoxidil.

It is a powerful arteriolar dilator. It is effective orally. It causes reflex tachycardia, Na + and water retention. Hence, minoxidil is used with a β-blocker and a diuretic. Topical minoxidil is used to promote hair growth in male type of baldness. (Minoxidil topical solution and spray are available.)

Diazoxide.

It is used in the treatment of hypertensive emergencies. It is administered intravenously and has a long duration of action (6–24 hours). It also relaxes uterine smooth muscle. Adverse effects are reflex tachycardia, hyperglycaemia, sodium and water retention.

Hydralazine.

It is a directly acting arteriolar dilator. It is administered orally. The side effects are reflex tachycardia, palpitation, sodium and water retention, which can be countered by combining hydralazine with a diuretic and a β-blocker. Other side effects are headache, hypotension, flushing, angina, MI, coronary steal phenomenon, etc. Immunological reactions, such as lupus syndrome, may occur.

Sodium nitroprusside.

It is a powerful arteriolar and venodilator (balanced arteriovenous dilator, Fig. 3.5 ). It is unstable, rapidly decomposes on exposure to light. So the solution should be prepared fresh; the infusion bottle and the entire drip set should be covered with black paper. It has a short duration of action, hence administered by i.v. infusion. It is rapid acting and dose is titrated according to response; tolerance does not develop to its action.

Fig. 3.5
Mechanism of action and effects of sodium nitroprusside.

Sodium nitroprusside is useful for treatment of hypertensive crisis; can also be used to improve CO in severe CCF. Nitroprusside can cause severe hypotension; hence, close monitoring of BP is required. Prolonged administration may cause anorexia, nausea, vomiting, fatigue, disorientation, toxic psychosis due to accumulation of cyanide, which in turn may lead to severe lactic acidosis and convulsions.

Nitroglycerin.

It is primarily a venodilator. Intravenous nitroglycerin is used in hypertension associated with acute LVF/MI. It acts rapidly but tolerance develops after prolonged infusion.

Fenoldopam

Fenoldopam is used in hypertensive emergencies and postoperative hypertension. Adverse effects include headache, flushing and reflex tachycardia.

Treatment of hypertension

  • 1.

    Nonpharmacological approaches helpful to control hypertension are weight reduction, sodium restriction, alcohol restriction, exercise, mental relaxation, cessation of smoking and consumption of potassium-rich diet.

  • 2.

    Drug treatment ( Tables 3.2 and 3.3 ): Selection of antihypertensive drugs in individual patients depends on: (i) comorbidity, (ii) associated complications, (iii) age, (iv) sex, (v) cost of the drug and (vi) concomitant drugs.

    • ■

      Preferred drugs for initial treatment of hypertension: ACE inhibitors, ARBs, CCBs and thiazides.

    • ■

      Therapy usually started with a single agent.

    • ■

      Combination therapy is used in patients who do not respond to single drug; can be used as initial therapy in patients with high BP.

    • Combination therapy: ACE inhibitors/ARBs with either thiazides/CCBs/diuretic. If response is not satisfactory, antihypertensives from other classes are added. ACE inhibitors are not to be combined with ARBs. A combination of non-DHPs (verapamil/diltiazem) with β-blocker should be avoided.

    Table 3.2 ■
    Dosage and indications of antihypertensive drugs
    Drug Dosage Indications
    Hydrochlorothiazide 12.5–25 mg o.d. oral Mild hypertension
    Chlorthalidone 12.5–25 mg o.d. oral Mild hypertension
    Captopril 12.5–75 mg b.d. oral Mild to severe hypertension – especially in diabetes patients
    Enalapril 2.5–40 mg o.d. oral Mild to severe hypertension – especially in diabetes patients
    Lisinopril 5–40 mg o.d. oral Mild to severe hypertension – especially in diabetes patients
    Ramipril 1.25–20 mg o.d. oral Mild to severe hypertension – especially in diabetes patients
    Losartan 25–50 mg o.d. or b.d. oral Mild to severe hypertension – especially in diabetes patients
    Propranolol 10–120 mg, b.d. or q.i.d. oral Mild to moderate hypertension
    Atenolol 25–100 mg o.d. oral Mild to moderate hypertension
    Nebivolol 2.5–5 mg o.d. oral Hypertension, congestive cardiac failure
    Prazosin 1–10 mg b.d. oral Mild to moderate hypertension
    Clonidine 0.05–0.6 mg b.d. Mild to moderate hypertension
    Sodium nitroprusside 0.25–1.5 mcg/kg/minute i.v. infusion in 5% dextrose Hypertensive emergencies (hypertensive crisis)
    Nifedipine SR 30–90 mg o.d. oral Mild to moderate hypertension
    Amlodipine 2.5–10 mg o.d. oral Mild to moderate hypertension
    α-Methyldopa 250 mg–2 g/day oral Hypertension during pregnancy
    Table 3.3 ■
    Commonly used drugs for hypertension associated with the following comorbid conditions
    Comorbid conditions Drugs
    Angina/post-MI β-Blockers, ACE inhibitors, ARBs
    Congestive cardiac failure/left ventricular failure ACE inhibitors, loop diuretics, ARBs
    Diabetes mellitus and diabetic nephropathy ACE inhibitors, ARBs, CCBs
    Poststroke (secondary prevention) ACE inhibitors, ARBs, thiazides
    Bronchial asthma/COPD Calcium channel blockers (CCBs)
    Hypertensive emergencies Sodium nitroprusside, labetalol, nitroglycerin
    Benign prostatic hyperplasia (BPH) Selective α 1 -blockers
    Pregnancy Nifedipine (sustained release), labetalol, α-methyldopa, hydralazine

Drugs to be avoided in specific conditions

Bronchial asthma/chronic obstructive pulmonary disease (COPD) Nonselective β-blockers
Peripheral vascular disease Nonselective β-blockers
Diabetes mellitus Nonselective β-blockers
Hyperlipidaemias Thiazides and β-blockers
Gout Thiazides
Sexually active males α 1 -Blockers and diuretics

Hypertensive crisis

Hypertensive emergency is characterized by a very high blood pressure (systolic > 180 and/or diastolic >120 mm Hg) with progressive end organ damage such as retinopathy, renal dysfunction and/or hypertensive encephalopathy. It is a medical emergency. If there is no end organ damage, it is hypertensive urgency. For hypertensive urgency, oral clonidine, labetalol or a DHP (e.g. amlodipine) is used.

In a patient with hypertensive emergency, the BP should be reduced by not more than 25% over 1 hour, then to 160/100 mm Hg over next 2–6 hours and to normal over next 48 hours. *

* Source: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

The drugs are administered intravenously – e.g. labetalol, nicardipine, nitroglycerin, sodium nitroprusside, furosemide (hypertensive crisis with acute pulmonary oedema), clevidipine, esmolol (in patients with aortic dissection), hydralazine, fenoldopam, enalaprilat, phentolamine (hypertensive crisis in pheochromocytoma), etc. Some of the regimens are described as follows:

  • Nicardipine: Start i.v. infusion with 5 mg/hour, increase by 2.5 mg/hour every 5 minutes to maximum 15 mg/hour. It is rapid acting and has a short duration of action. Reflex tachycardia can occur.

  • Labetalol: Start with 0.4–1.0 mg/kg/hour i.v. infusion up to 3 mg/kg/hour. It is avoided in patients with COPD/bronchial asthma/heart failure.

  • Sodium nitroprusside : Start i.v. infusion with 0.3–0.5 mcg/kg/minute; increase by 0.5 mcg/kg/minute to maximum dose 10 mcg/kg/minute. Monitor for cyanide toxicity (see p. 109).

Antianginal drugs PH1.28

Angina and myocardial infarction

Angina pectoris is a symptom of ischaemic heart disease.

Types of angina pectoris:

  • 1.

    Stable angina (classical angina): It is characterized by episodes of chest pain commonly associated with exertion.

  • 2.

    Unstable angina: It is characterized by angina at rest or increased frequency and duration of anginal attacks. In most cases, it is commonly due to rupture of an atheromatous plaque and platelet deposition in the coronary artery, leading to progressive thrombosis.

  • 3.

    Prinzmetal angina (variant angina): Angina that occurs at rest and is due to spasm of coronary arteries.

Pathophysiology.

Angina occurs due to imbalance in oxygen supply and oxygen demand by the myocardium.

Treatment.

Treatment is aimed at maintaining the balance between O 2 supply and demand.

Classification

  • 1.

    Nitrates: Nitroglycerin (glyceryl trinitrate), isosorbide dinitrate, isosorbide mononitrate, erythrityl tetranitrate, pentaerythritol tetranitrate.

  • 2.

    β-Adrenergic blockers: Propranolol, metoprolol, atenolol, timolol, bisoprolol.

  • 3.

    CCBs: Verapamil, diltiazem, nifedipine, felodipine, amlodipine, cilnidipine, nitrendipine nimodipine, lacidipine, lercanidipine.

  • 4.

    Potassium channel opener: Nicorandil.

  • 5.

    Others : *

    * Mnemonic: STAIR .

    A ntiplatelet agents (low-dose aspirin, clopidogrel, prasugrel), S tatins, T rimetazidine, R anolazine, I vabradine.

Organic nitrates

Organic nitrates are prodrugs – they release nitric oxide (NO). Nitrates are mainly venodilators, also cause arteriolar dilatation, thus reduce both preload and afterload.

Mechanism of action

Pharmacological actions of nitrates.

Nitroglycerin is the prototype drug. Nitrates have no direct action on the heart.

  • 1.

    On vascular smooth muscle: Nitroglycerin quickly relieves anginal pain by decreasing the O 2 requirement and increasing O 2 delivery to the myocardium.

  • 2.

    On other smooth muscles: Smooth muscles of the bronchi, oesophagus, biliary tract, etc. are relaxed by nitrates.

Pharmacokinetics.

Organic nitrates are readily absorbed through the buccal mucous membrane, skin and gastrointestinal (GI) tract. All nitrates except isosorbide mononitrate undergo extensive first-pass metabolism; hence, oral bioavailability of nitrates is very low. Sublingual route produces rapid onset (2–5 minutes) but short duration of action. Absorption through skin is slow; hence, transdermal route is used for a prolonged effect. The metabolites are excreted mainly in urine as glucuronide derivatives.

Adverse effects.

Adverse effects are due to extensive vasodilatation. They are headache, postural hypotension, tachycardia, palpitation, weakness, flushing and rarely syncope. To avoid these symptoms, the tablet may be spit out as soon as the pain is relieved. Overdosage may cause methaemoglobinaemia.

Tolerance.

Tolerance to nitrates occurs on prolonged use of nitrates orally/as transdermal patch/i.v. infusion. Development of tolerance is rare following intermittent exposure (e.g. sublingual glyceryl trinitrate [GTN]). Tolerance is due to decreased NO generation, depletion of sulphydryl radicals in the cell or generation of free radicals, etc. Nitrates also exhibit cross-tolerance. Tolerance can be prevented by giving a nitrate-free interval (8–12 hours) each day.

Isosorbide dinitrate.

It can be used sublingually for acute anginal attack and orally for chronic prophylaxis. Its oral bioavailability is low because of first-pass metabolism.

Isosorbide mononitrate.

It is preferred over dinitrate for chronic prophylaxis of angina, because it has:

  • ■

    Longer duration of action.

  • ■

    High oral bioavailability, as it does not undergo first-pass metabolism.

Therapeutic uses of nitrates

  • 1.

    Angina

    • (a)

      For acute attack of angina:

      • ■

        Nitroglycerin is the drug of choice. For an acute attack, nitroglycerin is commonly administered sublingually with an initial dose of 0.5 mg that usually relieves pain in 2–3 minutes. Patient is advised to spit out the tablet as soon as the pain is relieved to avoid side effects (hypotension and headache). If the pain is not relieved, the tablet can be repeated after 5 minutes but not more than three tablets in 15 minutes. Nitroglycerin undergoes extensive first-pass metabolism when swallowed. Nitroglycerin buccal spray can also be used for acute attack of angina.

      • ■

        Isosorbide dinitrate (sublingual) can also relieve acute attack of angina.

    • (b)

      For prophylaxis of angina: Longer acting nitrate preparations are used – isosorbide mononitrate orally; isosorbide dinitrate orally; nitroglycerin oral sustained-release preparation/ointment/disc/patch. Transdermal nitroglycerin produces prolonged effect, up to 24 hours ( Table 3.4 ). To avoid tolerance, the patch should be removed for a few hours (at least 8 hours). Oral nitrates are used for long-term prophylaxis of angina pectoris. They decrease the frequency of anginal attacks and improve exercise tolerance. Sublingual nitroglycerin may be used prophylactically, immediately before exercise or stress. The main disadvantage with long-term use of nitrates is development of tolerance which can be minimized by a nitrate-free interval of 8–10 hours/day.

      Table 3.4 ■
      Nitrates used in the treatment of angina
      Drug Dosage Duration of action
      Glyceryl trinitrate (GTN; nitroglycerin)
      • •

        0.5 mg (500 mcg) sublingual

      • •

        0.4 mg (400 mcg) lingual spray

      • •

        5–10 mg transdermal patch

      • •

        5–15 mg oral SR

      • •

        10–30 minutes

      • •

        10–30 minutes

      • •

        Up to 24 hours

      • Transdermal patch should be removed for few hours each day to avoid the development of tolerance

      Isosorbide dinitrate
      • •

        2.5–10 mg sublingual

      • •

        5–40 mg oral

      • •

        20–60 minutes

      • •

        6–8 hours

      Isosorbide mononitrate 20–40 mg oral 6–10 hours
      Erythrityl tetranitrate 20–40 mg oral 4–6 hours
      Pentaerythritol tetranitrate 80 mg oral 10–12 hours

  • 2.

    Variant angina (Prinzmetal angina): It is due to coronary vasospasm. Episodes of coronary vasospasm are treated with nitrates; for prophylaxis, nitrates and CCBs (amlodipine, nifedipine SR and diltiazem) are effective. Addition of a CCB with nitrate produces better efficacy in variant angina; also reduces the incidence of MI.

  • 3.

    Unstable angina: It requires treatment with multiple drugs.

    • (a)

      Antiplatelet agents: Low-dose aspirin, clopidogrel or prasugrel are used. Glycoprotein IIb/IIIa receptor antagonists (tirofiban, eptifibatide or abciximab) are useful in high-risk patients with acute coronary syndromes.

    • (b)

      Anticoagulants: Low-molecular-weight heparin, unfractioned heparin or fondaparinux.

    • (c)

      Nitrates: Nitroglycerin (sublingual) is usually effective. Intravenous nitroglycerin is administered if pain persists or recurs. Nitrates reduce myocardial oxygen consumption and relieve coronary vasospasm (BP should be monitored during i.v. infusion of nitroglycerin).

    • (d)

      β-Blockers: They (atenolol, metoprolol) are routinely administered in unstable angina unless contraindicated.

    • (e)

      CCBs: Amlodipine, nifedipine SR, diltiazem or verapamil are used if symptoms persist in patients on nitrates and β-blockers or if β-blockers are contraindicated.

    • (f)

      Statins: They have been shown to improve outcome in unstable angina.

  • 4.

    MI: For management of acute MI, intravenous infusion of nitroglycerin is useful for persistent or recurrent ischaemic pain and treatment of LV failure. It should be avoided if there is hypotension and in patients who received sildenafil or tadalafil in the past 24 hours.

  • 5.

    CCF: The role of nitrates in CCF is discussed on p. 124. Intravenous infusion of nitroglycerin is used mainly for acute heart failure. Monitoring of BP is necessary to avoid hypotension. Headache may limit the dose of nitrates.

  • 6.

    Hypertensive emergency: Intravenous infusion of nitroglycerin is used because of rapid onset of action, but the disadvantage is development of tolerance.

  • 7.

    Biliary colic: Sublingual nitroglycerin can be used to relieve biliary spasm and associated pain.

  • 8.

    Cyanide poisoning: In cyanide poisoning, the oxygen carrying capacity of blood is not affected. Cyanide inhibits cytochrome oxidase and prevents oxygen utilization by cells. All tissues suffer from anoxia (histotoxic type of anoxia).

Treatment of cyanide poisoning.

The main objective of treatment is to inactivate cyanide in the cells. In the absence of nitrites, cyanide binds to cytochrome oxidase causing inhibition of oxidative phosphorylation.

Step 1.

Amyl nitrite and sodium nitrite are used in the treatment of cyanide poisoning. Nitrites rapidly convert haemoglobin to methaemoglobin.

Step 2.

Methaemoglobin combines with cyanide to form nontoxic cyanomethaemoglobin.

Step 3.

Intravenous sodium thiosulphate converts cyanomethaemoglobin to sodium thiocyanate, which is rapidly excreted in urine.

Note.

Hydroxocobalamin can be used in cyanide poisoning. It binds cyanide to form cyanocobalamin.

β-adrenergic blockers

The beneficial effects of β-blockers in exertional angina are mainly due to negative chronotropic and negative inotropic effects.

β-Blockers have slow onset of action and are useful in anginal prophylaxis. β-Blockers improve exercise tolerance and reduce the frequency of anginal episodes. Use of β-blocker (those without intrinsic sympathomimetic activity) decreases mortality in patients with recent MI; hence, it should be started early and continued indefinitely. Cardioselective β-blockers are preferred. β-Blockers with intrinsic sympathomimetic activity (e.g. pindolol) should be avoided as they may worsen angina.

Adverse effects.

They include bradycardia, heart block, bronchospasm in patients with bronchial asthma, etc.

β-Blockers can increase LV end-diastolic volume.

This disadvantage of β-blockers can be counteracted by combining them with nitrates. β-Blockers can exacerbate cardiac failure, peripheral vascular disease and may precipitate bronchospasm in patients with bronchial asthma.

β-Blockers should not be withdrawn abruptly because this may precipitate dangerous arrhythmias or MI.

β-Blockers are contraindicated in variant angina which occurs due to coronary vasospasm. Coronary artery has α 1 - and β 2 -adrenergic receptors. Blockade of β 2 -receptors results in unopposed α 1 -mediated vasoconstriction and aggravation of variant angina.

Calcium channel blockers

  • 1.

    Phenylalkylamine: Verapamil.

  • 2.

    Benzothiazepine: Diltiazem.

  • 3.

    Dihydropyridines (DHPs): Nifedipine, amlodipine, cilnidipine, nicardipine, felodipine, isradipine, nisoldipine, lacidipine.

Mechanism of action.

Voltage-sensitive Ca 2+ channels are of five subtypes: L, N, T, P and R. L-type is predominantly present in cardiac and smooth muscle cells.

Pharmacological actions.

CCBs act mainly on cardiac and smooth muscles. They have little action on veins, hence do not alter preload.

  • 1.

    Verapamil: It is a phenylalkylamine and has predominant action on heart.

    • ■

      It decreases force of contraction (negative inotropic effect) and decreases heart rate (negative chronotropic effect). This reduces oxygen requirement of the myocardium.

    • ■

      It depresses SA node and slows AV conduction (negative dromotropic effect) by prolonging effective refractory period (ERP).

      • Verapamil is a less potent coronary and peripheral vasodilator than DHPs.

  • 2.

    Diltiazem: It dilates peripheral and coronary arteries but its vasodilating property is less marked than DHPs and verapamil. It also causes negative inotropic, chronotropic and dromotropic effects. It is used in the treatment of angina, hypertension and supraventricular arrhythmias.

  • 3.

    DHPs: These are potent arteriolar dilators and reduce peripheral vascular resistance. Higher doses are required for significant cardiac effects – cardiac depressant effect is less than verapamil and diltiazem.

    • (a)

      Nifedipine: It is the prototype drug. It has a predominant action on vascular smooth muscle. Reflex tachycardia and palpitation are commonly seen with nifedipine. This can be minimized by using sustained-release preparation or counteracted by adding a β-blocker.

    • (b)

      Amlodipine: It is absorbed slowly after oral administration. Palpitation and reflex tachycardia are less common with amlodipine. It is more potent and has a longer duration of action than nifedipine. It dilates both peripheral and coronary vessels. It has high oral bioavailability. It is mainly used in angina and hypertension. The common side effects are headache and ankle oedema. Reflex postcapillary constriction →↑ hydrostatic pressure → ankle oedema.

      • S (–) Amlodipine: It is an active S (–) enantiomer of amlodipine. It is more potent and causes less adverse effects.

    • (c)

      Nicardipine: Its antianginal effects are similar to nifedipine. It acts predominantly on coronary vessels.

    • (d)

      Felodipine: It has greater vascular selectivity than nifedipine and amlodipine. Like nifedipine, it can also produce tachycardia and palpitation.

    • (e)

      Lacidipine, lercanidipine and benidipine: They have long duration of action.

    • (f)

      Nimodipine: It has high lipid solubility, freely crosses BBB and selectively dilates cerebral blood vessels. It is used to prevent cerebral vasospasm and subsequent neurological defects in patients with subarachnoid haemorrhage.

    • (5)

      Cilnidipine : It blocks L-type and N-type calcium channels. Hence, reflex tachycardia and ankle oedema is less.

Pharmacokinetics.

All CCBs are well absorbed through GI tract but they undergo varying degree of first-pass metabolism. All are highly bound to plasma proteins, metabolized in liver and excreted in urine.

Adverse effects.

They are mentioned in Table 3.5 .

Table 3.5 ■
Adverse effects of calcium channel blockers
Nifedipine Verapamil Diltiazem
  • •

    Hypotension

  • •

    Palpitation

  • •

    Reflex tachycardia

  • •

    Oedema

  • •

    Flushing

  • •

    Fatigue

  • •

    Dizziness

  • •

    Sedation

  • •

    Constipation

  • •

    Sinus bradycardia

  • •

    Oedema; may precipitate CCF in patients with low cardiac reserve

  • •

    AV block and headache, rarely

  • •

    Headache

  • •

    Hypotension

  • •

    Bradycardia

  • •

    Oedema

  • •

    AV block occurs rarely

Uses of CCBs

  • 1.

    Exertional angina (for detailed explanation, see Pharmacological Actions): The beneficial effect in angina pectoris with CCBs is mainly due to a decrease in myocardial O 2 consumption (following ↓HR, ↓force of contraction or ↓afterload), and dilatation of coronary arteries. Diltiazem, verapamil and DHPs (amlodipine, nifedipine SR and nicardipine) are used in stable angina. Felodipine, isradipine and nisoldipine are also effective in angina. Diltiazem and verapamil produce less reflex tachycardia. Diltiazem is preferred to verapamil, as it has fewer side effects. DHPs like nifedipine and felodipine may aggravate anginal symptoms because of reflex tachycardia, which can be counteracted by combining them with β-blockers.

  • 2.

    Variant angina: It is due to coronary spasm. Amlodipine, nifedipine SR and diltiazem can be used prophylactically. They relieve pain effectively by attenuating the coronary vasospasm. Combined use of DHPs and nitrates has shown increased efficacy in patients with variant angina.

  • 3.

    Unstable angina: CCBs are used mainly when symptoms are not relieved by nitrates/β-blockers or if these drugs are contraindicated.

  • 4.

    Supraventricular arrhythmias: Verapamil is useful for supraventricular arrhythmias because of its depressant action on SA and AV nodes. It prolongs the refractory period and decreases the conduction velocity of AV node thereby reduces the ventricular rate in atrial flutter or atrial fibrillation. Diltiazem is also useful but is less effective than verapamil.

  • 5.

    Hypertension: DHPs, diltiazem and verapamil are used in hypertension. They control blood pressure by their vasodilatory effect. They can be safely used in hypertensive patients with asthma, hyperlipidaemia and renal dysfunction.

  • 6.

    Hypertrophic cardiomyopathy: Verapamil is the preferred CCB, as it improves diastolic function.

  • 7.

    Migraine: Verapamil is useful for prophylaxis of migraine. Another CCB, flunarizine, is more effective than verapamil in reducing the frequency of migraine attacks.

  • 8.

    Raynaud’s phenomenon: It is a peripheral vasospastic condition. Nifedipine, amlodipine, felodipine or diltiazem are used to treat this condition.

  • 9.

    Nifedipine is used as uterine relaxant in premature labour .

  • 10.

    Nimodipine is used for prevention and treatment of cerebral vasospasm and subsequent neurological defects in patients with subarachnoid haemorrhage.

Potassium channel openers (potassium channel activator)

Nicorandil is administered orally. It causes arteriolar and venodilation, and also improves coronary blood flow. Tolerance does not develop to its actions. The side effects are headache, hypotension, palpitation, flushing, nausea, vomiting, ulcers in the mouth, etc.

Other drugs

Antiplatelet agents.

Antiplatelet agent, aspirin 162 mg or 325 mg, is administered orally in patients with suspected or definite MI; if the patient is allergic to aspirin, clopidogrel 300 mg is administered. Antiplatelet agent should be continued once daily.

Statins.

See p. 139.

Ranolazine

  • ■

    Ischaemia increases the late inward sodium current in myocardium resulting in calcium influx and overload. Ranolazine inhibits late inward Na + current →↓ intracellular Ca 2+ overload in myocardium, contractility and oxygen consumption without altering heart rate and BP.

  • ■

    Used orally in chronic angina, it decreases the number of attacks and improves exercise tolerance.

  • ■

    QT prolongation may occur.

Trimetazidine

  • ■

    During ischaemia, the myocardium derives energy mainly from fatty acid oxidation which results in increased oxygen consumption. Trimetazidine → fatty acid oxidation inhibitor → partial inhibition of fatty acid oxidation in myocardium → increased use of glucose for energy → ↓ myocardial O 2 consumption.

  • ■

    Improves exercise tolerance and decreases frequency of anginal episodes.

  • ■

    Used orally in exertional angina in combination with other drugs.

Ranolazine is also an inhibitor of fatty acid oxidation.

Ivabradine

  • ■

    Site of action is SA node – heart rate is decreased → ↓ myocardial O 2 demand.

  • ■

    Decreases frequency of anginal episodes. It can also be used in sinus tachycardia.

Dipyridamole.

It dilates coronary blood vessels. It causes ‘coronary steal’ phenomenon by increasing blood flow to nonischaemic areas.

Combination therapy

  • 1.

    Nitrates × β-blockers (propranolol): This combination (used in exertional angina) increases the effectiveness and reduces the incidence of adverse effects ( Fig. 3.6 ).

    • (a)

      Nitrates can counteract the increase in LV end-diastolic volume associated with propranolol.

    • (b)

      Nitrates → arteriolar dilatation →↓ PVR → reflex tachycardia. Propranolol can block the reflex tachycardia that is associated with nitrates.

    • (c)

      • Nitrates can prevent the coronary spasm associated with β-blockers.

    Fig. 3.6
    Effects of nitrates × β-blockers (propranolol).

  • 2.

    Nifedipine (DHPs) × β-blockers: β-Blockers can block the reflex tachycardia that is associated with nifedipine ( Fig. 3.7 ). Coronary vasospasm by β-blockers is prevented. Slow-acting DHPs are also combined with β-blockers. The combination is useful in classical angina with associated coronary vasospasm.

    Fig. 3.7
    Effects of nifedipine (DHPs) × β-blockers.

  • 3.

    β-Blockers × verapamil/diltiazem: This combination should not be used as it may cause additive depressant effect on SA node, AV node and cardiac contractility leading to heart block, heart failure or even cardiac arrest.

  • 4.

    CCBs × nitrates: The net effect is an additive reduction in the myocardial O 2 demand and improved coronary blood flow ( Fig. 3.8 ). This combination is useful in severe variant angina.

    Fig. 3.8
    Effects of calcium channel blockers + nitrates.

  • 5.

    Nitrates × β-blockers × CCBs: This combination is especially useful in severe and resistant cases of exertional angina and also in unstable angina ( Fig. 3.9 ).

    Fig. 3.9
    Effects of nitrates + β-blockers + CCBs.

  • 6.

    Sildenafil/tadalafil (PDE-5 inhibitors) × nitrates: Sildenafil potentiates vasodilator action of nitrates; can cause MI and sudden death. Nitrates should be avoided for 24 hours after sildenafil intake.

Pharmacotherapy of acute myocardial infarction

  • 1.

    Antiplatelet agent: Aspirin, 162 mg or 325 mg orally (chewed and swallowed), is administered at once to a patient with suspected or definite MI. If the patient is allergic to aspirin, clopidogrel 300 mg is administered. Antiplatelet agent should be continued once daily.

  • 2.

    Analgesia: Intravenous morphine 10 mg for relief of pain. Antiemetics like promethazine 25–50 mg slow i.v. to prevent opioid-induced vomiting.

  • 3.

    Nitrates: Intravenous nitroglycerin for recurrent or persistent pain and to treat LV failure.

  • 4.

    Low flow oxygen therapy (2–4 L/minute) if there is decreased oxygen saturation.

  • 5.

    Reperfusion therapy: Primary percutaneous coronary intervention (PCI) or thrombolytic therapy.

    • ■

      Primary PCI, if facilities are available.

    • ■

      Thrombolytic therapy: Streptokinase, alteplase, tenecteplase, reteplase or urokinase is used to restore coronary patency and reperfusion of infarcted area.

  • 6.

    Anticoagulants: Low-molecular-weight heparin or unfractionated heparin is given to prevent reinfarction and thromboembolic complications.

  • 7.

    β-Blockers should be administered during first 24 hours unless contraindicated. They prevent reinfarction, arrhythmias and reduce mortality.

  • 8.

    ACE inhibitors (e.g. ramipril) or angiotensin receptor blockers (e.g. valsartan) are administered early to improve survival.

  • 9.

    Statins (e.g. atorvastatin) should be started (secondary prevention) to reduce thrombotic events and reinfarction.

  • 10.

    Acidosis is treated with intravenous sodium bicarbonate.

Drugs used in congestive cardiac failure PH1.29

The function of the heart is to pump an adequate amount of blood to various tissues. In CCF, there is an inadequate or inefficient contraction of the heart leading to reduced CO. In initial stages of CCF, the compensatory mechanisms that try to maintain the CO ( Fig. 3.10 ) are as follows:

  • ■

    Increased sympathetic activity.

  • ■

    Increased renin–angiotensin–aldosterone activity.

  • ■

    Myocardial hypertrophy and remodelling.

Fig. 3.10
Pathophysiology of CCF and mechanism of action of some drugs used in its treatment. ARBs, angiotensin receptor blockers; CCF, congestive cardiac failure; CO, cardiac output.

As time progresses, the compensatory mechanisms fail and gradually clinical symptoms of failure appear. The basic haemodynamic disturbances seen in CCF are as follows:

  • ■

    Increased pulmonary capillary pressure termed as backward failure, which is characterized by dyspnoea and orthopnoea.

  • ■

    Decreased CO termed as forward failure, leading to decreased oxygen supply to the peripheral tissues (tissue hypoxia).

The goal of therapy is to provide relief from symptoms, slow the progression of disease and decrease mortality. The treatment strategies for CCF include preload reduction, afterload reduction and enhancement of contractile state of the heart.

Classification

  • 1.

    Diuretics:

    • (a)

      Loop diuretics: Furosemide, bumetanide, torsemide.

    • (b)

      Thiazide diuretics: Chlorothiazide, hydrochlorothiazide, metolazone.

    • (c)

      Aldosterone antagonists: Spironolactone, eplerenone.

  • 2.

    Vasodilators:

    • (a)

      Arteriolar and venodilators:

      • ■

        ACE inhibitors: Enalapril, lisinopril, ramipril, fosinopril, trandolapril.

      • ■

        Angiotensin receptor blockers (ARBs): Losartan, candesartan, valsartan, telmisartan.

      • ■

        Direct renin inhibitor: Aliskiren.

      • ■

        Sodium nitroprusside.

    • (b)

      Venodilators : Nitroglycerin, isosorbide dinitrate.

    • (c)

      Arteriolar dilators: Hydralazine, minoxidil, nicorandil.

  • 3.

    β-Adrenergic blockers : Metoprolol, bisoprolol, carvedilol, nebivolol.

  • 4.

    Sympathomimetic amines : Dopamine, dobutamine.

  • 5.

    Cardiac glycosides: Digoxin.

  • 6.

    Phosphodiesterase 3 inhibitors : Inamrinone, milrinone.

  • 7.

    Vasopressin-receptor antagonists: Tolvaptan, conivaptan.

  • 8.

    Neprilysin inhibitor: Sacubitril

  • 9.

    Brain natriuretic peptide (BNP): Nesiritide.

Diuretics

A majority of patients with CHF are started on diuretics.

Therapy is initiated with a loop diuretic – oral furosemide/torsemide/bumetanide. Furosemide is the commonly used loop diuretic. Torsemide and bumetanide are better absorbed than furosemide. In severe HF, i.v. diuretic is required. Thiazides can be added to loop diuretics in advanced cases of HF for synergistic effect. Serum K + levels should be monitored. Volume contraction should be avoided. Aldosterone antagonist can be added to loop diuretic in moderate to severe HF to increase diuretic efficacy, counteract K + loss and improve survival. Long-term treatment with diuretics may be required to prevent fluid retention and recurrent oedema.

Vasodilators

The vasodilators may be classified according to the distribution of their effect:

  • 1.

    Mixed arteriolar and venodilators: ACE inhibitors, ARBs, sodium nitroprusside, reduce both preload and afterload.

  • 2.

    Drugs with predominant venodilatory effect ( Fig. 3.11 ): Nitrates reduce preload; they also have some effect on arterioles.

    Fig. 3.11
    Effects of vasodilators in congestive cardiac failure.

  • 3.

    Drug with predominant arteriolar dilating effect ( Fig. 3.11 ): Hydralazine, minoxidil, etc. reduce afterload.

ACE inhibitors.

They are the standard therapy for all grades of CHF and asymptomatic LV systolic dysfunction. They inhibit conversion of angiotensin I to angiotensin II. ACE inhibitors inhibit the generation of angiotensin II resulting in the following:

  • ■

    Decrease in peripheral vascular resistance → increase in stroke volume → improved tissue perfusion. Increase in renal blood flow → diuresis →↓circulating blood volume.

  • ■

    Decrease in aldosterone production → decrease in sodium and water retention →↓ preload.

  • ■

    Venodilation →↓preload.

  • ■

    There is decrease in pressure in atria and pulmonary circuit.

  • ■

    Retard/reverse ventricular hypertrophy and remodelling by decreasing angiotensin II and aldosterone levels.

    • Therapy with ACEIs leads to symptomatic improvement, decreased hospitalization and mortality and slowing down of disease progression.

For mechanism of action, adverse effects and contraindications, see pp. 100–102.

Angiotensin receptor blockers (p. 103).

Losartan, candesartan, etc. competitively block AT 1 -receptors on the heart, peripheral vasculature and kidney. They prevent the effects of angiotensin II and produce effects similar to those of ACE inhibitors. Angiotensin receptor blockers are mainly used in patients who cannot tolerate ACE inhibitors because of cough, angioedema and neutropenia.

Direct renin inhibitor.

Aliskiren, a direct renin inhibitor, produces a decrease in plasma renin, angiotensin I and II levels. This decreases BP, LV mass and may produce beneficial effects in heart failure.

Other vasodilators ( Fig. 3.11 ):

Sodium nitroprusside (i.v.) and nitroglycerin (i.v.) are used for severe heart failure. Hydralazine , an arteriolar dilator, increases CO in patients with heart failure. The disadvantages with the use of arteriolar dilators are reflex tachycardia and fluid retention. Tachycardia is rare with mixed arteriolar and venodilators.

β-adrenergic blockers

β-Blockers like metoprolol, bisoprolol, carvedilol and nebivolol are useful in mild to moderate heart failure. Long-term therapy with these β-blockers improves symptoms, reduces hospitalization and decreases mortality in patients with mild to moderate heart failure. The exact mechanism of action is not clear. They block β-receptor–mediated effects of catecholamines on the heart. This improves LV structure and function, decreases wall stress, increases ejection fraction and decrease LV size. They decrease apoptosis and ventricular remodelling. They also decrease frequency of arrhythmias. The antioxidant effect of carvedilol also contributes to its beneficial effects. Therapy with β-blockers in heart failure should be under careful supervision.

Cardiac glycosides

Chemistry.

The glycosides consist of an aglycone (steroid nucleus with an attached lactone ring) with one or more sugar moieties attached to it. They have a potent action on the heart, hence are referred to as cardiac glycosides. The utility of digitalis in the treatment of heart failure was shown by William Withering.

Sources

Source Glycosides
Digitalis purpurea (leaf) Digitoxin
Digitalis lanata (leaf) Digoxin, digitoxin
Strophanthus gratus (seed) Strophanthin-G (ouabain)

Mechanism of action of cardiac glycosides (digitalis; fig. 3.12 ).

Na + K + -ATPase is a membrane-bound enzyme which is called digitalis receptor. It is also called sodium pump.

Fig. 3.12
Mechanism of action of cardiac glycosides: SR, sarcoplasmic reticulum.

Pharmacological actions

  • 1.

    Cardiac

  • 2.

    Extracardiac

Cardiac actions.

Digitalis has direct and indirect actions on the heart.

  • ■

    Direct action by inhibiting Na + K + -ATPase

  • ■

    Indirect action by stimulating vagus (vagomimetic effect)

    • 1.

      Myocardial contractility: Digitalis increases the force of contraction of the myocardium (positive inotropic effect). This effect is more prominent in the failing heart. Digitalized heart contracts more forcibly and completely. The positive inotropic effect causes complete emptying of the ventricles during systole and increases the CO. This decreases pulmonary congestion and systemic venous pressure. The diastolic size of the heart is reduced. When the size of the heart is reduced, muscle fibre length is also reduced, thereby, decreasing the oxygen requirement of myocardium. The digitalized heart, thus, can do more work for the same energy. Therefore, digitalis is called a ‘cardiotonic’.

    • 2.

      Heart rate: In patients with CCF, digitalis reduces the heart rate (negative chronotropic effect) by direct and indirect actions. In small doses, digitalis decreases heart rate by stimulation of vagus. In toxic doses, it can increase sympathetic activity thus increasing heart rate.

    • 3.

      Electrophysiological actions: At therapeutic concentrations, digoxin decreases automaticity and increases resting membrane potential by vagal action in atria and AV node. It also prolongs ERP and decreases conduction velocity in AV node. This may lead to bradycardia and AV block. At higher concentrations, digoxin can increase automaticity in cardiac tissue by direct action as well as by increasing sympathetic activity. This can result in atrial and ventricular arrhythmias.

    • 4.

      ECG: Digitalis produces prolongation of P-R interval, inversion of T wave and depression of ST segment.

Extracardiac actions

  • 1.

    Gastrointestinal tract (GIT): Digitalis can produce anorexia, nausea, vomiting and occasionally diarrhoea. Nausea and vomiting are due to stimulation of chemoreceptor trigger zone (CTZ) and a direct action on the gut.

  • 2.

    Kidney: In patients with CCF, digitalis causes diuresis (increased urine output).

  • 3.

    Central nervous system (CNS): In high doses, it can cause central sympathetic stimulation, confusion, blurring of vision, disorientation, etc.

Pharmacokinetics.

Digoxin is the commonly used glycoside and is usually administered by oral route; food delays the absorption of digoxin. It is widely distributed in the body, concentrated in the heart, liver, kidney and skeletal muscle. It crosses BBB and is mainly excreted unchanged in urine. Dosage adjustment of digoxin is necessary in patients with renal failure.

Adverse effects.

Digoxin has a narrow margin of safety. Monitoring of serum digoxin, electrolyte levels and electrocardiogram (ECG) are important during digitalis therapy.

  • 1.

    Extracardiac

    • (a)

      GIT: Early symptoms of toxicity are anorexia, nausea and vomiting, which are due to GI irritation and CTZ stimulation.

    • (b)

      CNS effects include headache, confusion, restlessness, disorientation, weakness, visual disturbances, altered mood and hallucinations.

    • (c)

      Skin rashes and gynaecomastia can occur occasionally.

  • 2.

    Cardiac: Digitalis can cause any type of arrhythmias. The most common are ventricular premature beats, pulsus bigeminy and ventricular tachycardia. It can also cause AV block, atrial tachycardia, atrial fibrillation, atrial flutter and even severe bradycardia.

Factors affecting digitalis toxicity

  • 1.

    Age: Elderly patients are more susceptible to digitalis toxicity due to declining renal and hepatic function.

  • 2.

    Route: Intravenous digitalization carries more risk than oral route.

  • 3.

    Hypokalaemia increases the binding of digoxin to Na + K + -ATPase and enhances its toxicity.

  • 4.

    Hypercalcaemia and hypomagnesaemia enhance digoxin toxicity.

  • 5.

    Hypothyroidism, hyperthyroidism, hypoxia, renal failure and myocarditis are predisposing factors to digitalis toxicity.

Treatment of digoxin toxicity

  • 1.

    Shift the patient to intensive care unit (ICU).

  • 2.

    Stop digoxin and potassium-depleting diuretics (thiazides/loop diuretics).

  • 3.

    Potassium chloride (KCl) orally or intravenously is the drug of choice for tachyarrhythmias, when serum K + level is normal/low.

  • 4.

    Supraventricular arrhythmias are treated with oral or intravenous propranolol.

  • 5.

    Intravenous lignocaine is the drug of choice for ventricular arrhythmias because it has:

    • ■

      Relatively low incidence of toxicity.

    • ■

      A rapid onset and short duration of action, so its action wears off immediately after stopping the infusion.

    • ■

      No action on AV nodal conduction velocity, hence, does not intensify the AV block in digitalis toxicity.

  • 6.

    AV block and bradyarrhythmias are treated with atropine and cardiac pacing.

  • 7.

    Digoxin antibodies (Digibind): It is used only in case of serious digitalis toxicity. It neutralizes circulating digoxin/digitoxin and rapidly reverses the toxicity, but it is expensive.

Drug interactions

  • 1.

    Cholestyramine/colestipol × digoxin : Cholestyramine and colestipol (bile acid binding resins) bind to cardiac glycosides in the gut and reduce its absorption.

  • 2.

    β-blocker/verapamil × digoxin : These drugs have additive depressant effect on SA and AV nodes and may precipitate AV block.

  • 3.

    Thiazides/loop diuretics × digoxin : Hypokalaemia caused by diuretics, may potentiate digoxin toxicity. Hypokalaemia increases the binding of digoxin to Na + K + -ATPase.

  • 4.

    Calcium × digoxin : Calcium increases the incidence of digoxin toxicity.

  • 5.

    Digoxin × sympathomimetic/succinylcholine : The chances of cardiac arrhythmias are more with sympathomimetic/succinylcholine in patients on digoxin.

Uses of digitalis

  • 1.

    CCF: Digitalis is useful in patients with low output failure, especially when associated with atrial fibrillation. It is ineffective in high output failure associated with severe anaemia, thyrotoxicosis and AV shunt.

    • The beneficial effects of digoxin in case of heart failure are due to its action on myocardium (positive inotropic effect), venous system and kidney ( Fig. 3.13 ).

      • For explanation, see Pharmacological Actions.

      Fig. 3.13
      Beneficial effects of digitalis in CCF. CO, cardiac output.

  • 2.

    Atrial fibrillation: It is the most common cardiac arrhythmia. In atrial fibrillation, the atria beat at a rate of 350–600/minute. Digitalis has both direct and indirect (vagomimetic) actions on AV node. It depresses AV node by increasing ERP and decreasing conduction velocity, thus reduces the ventricular rate. Verapamil and propranolol can be used in atrial fibrillation.

  • 3.

    Atrial flutter: In atrial flutter, the atria beat rapidly at a rate of about 300/minute. Digitalis controls ventricular rate by depressing AV conduction.

  • 4.

    Paroxysmal supraventricular tachycardia (PSVT): In PSVT, the heart rate is about 140–220/minute. The preferred drug for PSVT is adenosine. Propranolol or verapamil can also be used. Digoxin has a slower onset of action hence it is not suitable for acute therapy. Digoxin is preferred in PSVT, if there is associated heart failure. It terminates the arrhythmia by increasing the vagal tone.

Sympathomimetic amines

Dopamine and dobutamine are used in acute heart failure. They have positive inotropic effect and provide symptomatic relief in patients with ventricular dysfunction.

Dopamine.

It is a catecholamine and has dose-dependent haemodynamic effects. At low doses (<2 mcg/kg/minute), dopamine selectively dilates renal, mesenteric and coronary blood vessels by acting on D 1 -receptors. Thus, dopamine increases GFR and urine output. At moderate doses (2–5 mcg/kg/minute), dopamine stimulates β 1 -receptors of heart, increases myocardial contractility and CO but tachycardia is less prominent. It also stimulates dopaminergic receptors resulting in an increase in GFR. Dopamine (i.v. infusion) is used in cardiogenic shock and acute heart failure with renal impairment. It improves both cardiac and renal function. At high concentration (>10 mcg/kg/minute), it causes generalized vasoconstriction. This increases afterload and reduces blood flow to renal, mesenteric and other vital organs. So the beneficial effects seen with low to moderate doses of dopamine are lost at higher concentrations.

Dobutamine.

It is a synthetic catecholamine and acts on β 1− , β 2− and α 1 -receptors. It has selective inotropic effect and increases CO. In therapeutic doses, it has little effect on BP and heart rate. Total peripheral resistance is generally not affected. This is due to counterbalancing of α 1 -receptor–mediated vasoconstriction and β 2 -receptor–mediated vasodilatation. It is administered by i.v. infusion for short-term treatment of acute heart failure (due to MI or cardiac surgery) and cardiogenic shock. The side effects are tachycardia, rise in BP and development of tolerance.

Aldosterone antagonists

Increased aldosterone levels in CHF causes salt and water retention → increased preload; potassium excretion can cause hypokalaemia → increased risk of arrhythmias. Aldosterone also causes ventricular remodelling and hypertrophy. Spironolactone/eplerenone blocks action of aldosterone on its receptor and blocks these effects. They slow disease progression and decrease mortality. They are used in combination with other drugs in moderate to severe heart failure.

Phosphodiesterase 3 inhibitors

Inamrinone and milrinone are selective phosphodiesterase 3 (PDE-3) inhibitors and increase cAMP level. They exert both positive inotropic and vasodilator actions (inodilators). They are administered intravenously. They increase CO and decrease afterload. They are used for short-term treatment of severe heart failure. The adverse effects of inamrinone include nausea, vomiting, arrhythmias, thrombocytopenia and hepatotoxicity. Milrinone is more potent than inamrinone and does not produce thrombocytopenia.

Vasopressin-receptor antagonists

Short-term therapy with tolvaptan may improve symptoms in CHF with volume overload and severe hyponatraemia.

Natriuretic peptide

Nesiritide, recombinant form of brain natriuretic peptide (BNP), is useful in acute decompensated heart failure. Dyspnoea is reduced. It is a vasodilator and is administered intravenously. Hypotension is a common adverse effect.

Sacubitril

It inhibits neprilysin → inhibits metabolism of ANP (atrial natriuretic peptide) and BNP → vasodilation and diuresis. It is used in combination with valsartan for severe heart failure

Management of CCF include Diet (salt restriction), Diuretics, Dilators (vasodilators–ACEIs, ARBs), Digoxin, Dopamine, Dobutamine, PDE-3 inhibitors, etc. (note the ‘Ds’) and beta-blockers. ACEIs, ARBs, aldosterone antagonists, sacubitril and β-blockers slow down the progression of disease. Symptoms of congestion are relieved by vasodilators, diuretics, dobutamine, dopamine, digoxin, milrinone and inamrinone.

Antiarrhythmic drugs PH1.30

Cardiac electrophysiology

The transmembrane potential of a cardiac cell at rest is about −90 mV negative to the exterior. This is determined mainly by sodium, potassium, calcium and chloride ions.

Ionic distribution

Normally

  • ■

    K + is more in the intracellular fluid (ICF) than extracellular fluid (ECF).

  • ■

    Na + , Ca 2+ and Cl − are more in the ECF.

Cardiac action potential

Normally, an impulse is generated in the SA node. From SA node → atria → AV node (slowly) → bundle of His → ventricles.

The action potential of Purkinje system has five phases ( Fig. 3.14 ):

  • ■

    Phase 0 (rapid depolarization): It is mainly due to rapid influx of Na + through open sodium channels. The upstroke stops following inactivation of sodium channels.

  • ■

    Phase 1 (period of early fast repolarization): It occurs due to stoppage of inward flow of Na + and start of K + outflow from the cell. It lasts for a brief period.

  • ■

    Phase 2 (plateau phase): During this phase, Ca 2+ enters the myocardial cell through voltage-dependent slow Ca 2+ channels whereas K + moves out of the cells through potassium channels.

  • ■

    Phase 3 (phase of repolarization): Calcium channel closes; efflux of K + occurs throughout this phase.

  • ■

    Phase 4 (spontaneous depolarization): The membrane potential returns to the resting value. In the Purkinje fibres, there is spontaneous depolarization.

Fig. 3.14
Cardiac action potential. TP, threshold potential. RP, resting potential; PHASE 0, rapid depolarization; PHASE 1, early fast repolarization; PHASE 2, plateau phase; PHASE 3, repolarization; PHASE 4, spontaneous depolarization.

In the SA and AV node, phase 0 is due to slow inflow of Ca 2+ ions through activated Ca 2+ channels. These cells also undergo spontaneous depolarization like Purkinje fibres. Spontaneous depolarization results from depolarizing currents due to flow of Na + , Ca 2+ and K + ions.

In atria and ventricles, the membrane potential is steady during diastole. The duration of atrial action potential is shorter than that of ventricles.

Properties of a cardiac cell

  • ■

    Automaticity: It is the ability of the cardiac cell to undergo spontaneous depolarization. Normally, the rate of spontaneous depolarization is fastest in SA node; hence, it is the pacemaker of the heart.

  • ■

    Excitability: It is the ability of a cell to undergo depolarization in response to a stimulus.

  • ■

    Threshold potential: It is the potential at which sudden, rapid and complete depolarization occurs resulting in the generation of an action potential.

  • ■

    Conduction velocity: It depends mainly on the slope of action potential and phase 0 depolarization.

  • ■

    Effective refractory period (ERP): It is the minimal interval between two successive, propagated action potentials.

Arrhythmias

Arrhythmias are disturbances in cardiac rhythm (i.e. abnormality in site of origin of impulse, its rate, regularity or conduction). Arrhythmias can be either tachyarrhythmias or bradyarrhythmias.

  • ■

    Bradyarrhythmias may be due to reduced automaticity or abnormal slowing/blockade of impulse conduction.

  • ■

    Tachyarrhythmias are due to either increased automaticity, after depolarization or re-entry of an impulse.

Various cardiac arrhythmias are atrial flutter, atrial fibrillation, PSVT, ventricular tachycardia, ventricular fibrillation, torsades de pointes, AV block, etc.

Drugs used to restore normal rhythm are known as antiarrhythmic drugs.

Classification of antiarrhythmic drugs (vaughan–williams)

  • ■

    Class I: Na + channel blockers (membrane stabilizing agents)

    • ■

      IA: Drugs that moderately depress phase 0 depolarization – quinidine, procainamide, disopyramide.

    • ■

      IB: Drugs that have minimal effect on phase 0 depolarization – lignocaine, mexiletine.

    • ■

      IC: Drugs that markedly depress phase 0 depolarization – flecainide, propafenone.

  • ■

    Class II ( β-adrenergic blockers): Propranolol, atenolol, esmolol, metoprolol, sotalol.

  • ■

    Class III (drugs that prolong duration of action potential): Amiodarone, dronedarone, sotalol, dofetilide, ibutilide, bretylium.

  • ■

    Class IV (CCBs): Verapamil, diltiazem.

Other antiarrhythmic agents are digoxin, adenosine, atropine, isoprenaline, etc.

Class I: Na + channel blockers

Quinidine.

It is a class IA antiarrhythmic drug. It is an alkaloid obtained from cinchona bark.

Pharmacological actions of quinidine

  • 1.

    Cardiovascular system

    • (a)

      Heart:

      • ■

        Quinidine blocks Na + channels in the open state → decreases automaticity, excitability, rate of phase 0 depolarization and conduction velocity.

      • ■

        It blocks potassium channels → increases duration of action potential.

      • ■

        It prolongs ERP as a result of blockade of both Na + and K + channels.

      • It suppresses ectopic foci and blocks re-entry of impulses.

    • (b)

      AV node: Effect on AV node conduction is variable. It has vagolytic (increases AV node conduction) and direct depressant action on AV node.

    • (c)

      ECG: Quinidine prolongs QRS complex and QT interval.

    • (d)

      BP: Quinidine causes fall in blood pressure due to α-adrenergic blocking and direct myocardial depressant effects.

  • 2.

    Skeletal muscles: Quinidine reduces skeletal muscle contraction.

  • 3.

    Others: It also has antimalarial, antipyretic and oxytocic activities.

Pharmacokinetics.

Quinidine is well absorbed from GI tract, highly bound to plasma proteins, metabolized in liver, and about 20% is excreted unchanged in urine.

Adverse effects.

The important adverse effects are diarrhoea, thrombocytopenia and fall in BP and torsades de pointes . Hepatitis and fever can rarely occur. Large doses of quinidine may produce a syndrome called ‘cinchonism’. The manifestations are tinnitus, deafness, headache, blurring of vision, diplopia, photophobia, confusion, delirium, disorientation and psychosis.

Drug interactions

  • 1.

    Quinidine may potentiate the effects of neuromuscular blocking drugs.

  • 2.

    Quinidine × β-blockers/verapamil/potassium salts: Additive cardiac depressant effect may lead to cardiac arrest.

Uses.

Quinidine has a broad spectrum of antiarrhythmic activity but it is not the drug of choice in any type of arrhythmias. Its use has declined because of its adverse effects and availability of better antiarrhythmic drugs. It is useful in maintaining normal sinus rhythm in patients with atrial fibrillation or atrial flutter and occasionally to treat ventricular tachycardia.

Procainamide.

Like quinidine, procainamide is also a class IA antiarrhythmic drug. Its effects are similar to those of quinidine but it has no anticholinergic and α-adrenergic blocking effects.

Pharmacokinetics.

Procainamide is well absorbed after oral administration. It can also be given by i.v. and i.m. routes. It is metabolized in liver by acetylation. The major metabolite is N -acetyl procainamide (NAPA) that has K + channel–blocking activity. NAPA is excreted in urine; hence dosage adjustment may be needed in patients with renal failure.

Adverse effects

  • 1.

    CVS: Hypotension (due to ganglion blockade) and heart block are the main adverse effects following i.v. administration. Torsades de pointes can also occur.

  • 2.

    GIT: Nausea and vomiting.

  • 3.

    CNS: Mental confusion, depression, hallucinations and psychosis. Long-term procainamide therapy often produces lupus-like syndrome with arthralgia and arthritis.

Uses.

It is useful in ventricular arrhythmias associated with acute MI. It is not used for long-term oral therapy due to need for frequent dosing and risk of lupus syndrome.

Disopyramide.

It is a class IA antiarrhythmic drug. Its actions are similar to those of quinidine but it has more marked anticholinergic action.

Pharmacokinetics.

Disopyramide is well absorbed after oral administration. It is partly metabolized in liver and partly excreted in urine in the unchanged form.

Uses.

Disopyramide is mainly used for the treatment of ventricular arrhythmias. It can also be used to maintain sinus rhythm in patients with atrial fibrillation or atrial flutter.

Adverse effects.

Anticholinergic side effects are urinary retention especially in benign prostatic hyperplasia (BPH), dryness of mouth, blurring of vision, constipation, precipitation of an attack of glaucoma, etc.

Lignocaine.

Lignocaine is a local anaesthetic having antiarrhythmic activity. It is a class IB antiarrhythmic drug. Local anaesthetic preparation of lignocaine contains methylparaben, a preservative, hence not used as antiarrhythmic agent.

Pharmacological actions.

It blocks sodium channels in the inactivated (predominantly) and the active states. It has minimal effect on normal cardiac tissues. Its effect is prominent in depolarized (ischaemic) tissues. It decreases automaticity of ectopic foci by reducing the slope of phase 4 depolarization and depresses conduction in depolarized (diseased) tissue. Action potential duration is usually unaffected or may be shortened.

Pharmacokinetics.

Lignocaine is orally not effective because of extensive first-pass metabolism. Lignocaine is, therefore, commonly administered by intravenous route as an antiarrhythmic. It is widely distributed in the body, readily crosses BBB, is poorly bound to plasma proteins, rapidly metabolized in liver and has short plasma half-life of 1–2 hours. The volume of distribution and hepatic clearance of lignocaine are reduced in patients with heart failure; hence, both the loading and maintenance dose should be decreased. In hepatic disease, the clearance of lignocaine is reduced; hence, it requires a reduction in the maintenance dose.

Drug interactions.

Lignocaine × propranolol: Propranolol reduces lignocaine elimination by reducing the hepatic blood flow, thus increases the risk of lignocaine toxicity.

Adverse effects.

These are mainly related to the central nervous system – headache, drowsiness, nystagmus, blurred vision, confusion, muscle twitchings and convulsions. In high doses, lignocaine may cause hypotension due to myocardial depression. Side effects are potentiated in renal and hepatic failure.

Uses

  • ■

    Lignocaine is used for emergency treatment of ventricular arrhythmias associated with MI, digitalis toxicity and cardiac surgery.

  • ■

    Lignocaine is preferred in ventricular arrhythmias because it:

    • ■

      Is relatively less toxic.

    • ■

      Has a rapid onset and short duration of action, so its action wears off immediately after stopping the infusion.

    • ■

      Has no action on AV nodal conduction velocity, hence does not intensify the AV block during treatment of ventricular arrhythmias in digitalis toxicity.

  • ■

    Lignocaine is administered intravenously initially as bolus 1–2 mg/kg and later 1–4 mg/minute i.v. infusion as maintenance dose.

  • ■

    Lignocaine is not useful in atrial arrhythmias because atrial action potentials are of very short duration – so the Na + channels are in the inactivated state for a very brief period of time.

Mexiletine.

It is an analogue of lignocaine and has similar actions. It is used orally and parenterally in the treatment of ventricular arrhythmias. The common adverse effects are nausea, dizziness and tremors.

Flecainide and propafenone.

These are class IC antiarrhythmic drugs. They block sodium channels in the open state. Class IC drugs have the most potent blocking effect on sodium channels. They markedly depress phase 0 depolarization, slow conduction and prolong PR interval. Propafenone also blocks β receptors.

Adverse effects.

Both the drugs can exacerbate arrhythmias and CCF. Other adverse effects seen with propafenone are metallic taste, constipation, bradycardia and bronchospasm. Blurring of vision is common with flecainide.

Uses.

Propafenone and flecainide are primarily used for the treatment of supraventricular arrhythmias; can also be used in ventricular arrhythmias. Both the drugs are administered orally.

Class II: β-blockers.

Propranolol, atenolol, esmolol, metoprolol, etc. are class II antiarrhythmic agents. They block the effects of catecholamines on the heart. They:

  • ■

    Depress the phase 4 depolarization – decrease automaticity in SA node and ectopic foci (when increased by adrenergic stimulation).

  • ■

    Prolong the refractory period and decrease the conduction velocity in AV node which makes them useful:

    • ■

      In the treatment of re-entrant arrhythmias involving the AV node (PSVT).

    • ■

      To control ventricular rate in atrial flutter and atrial fibrillation.

In high doses, propranolol has ‘quinidine-like’ membrane stabilizing effect.

Pharmacokinetics, adverse effects and contraindications are discussed on pp. 93–95.

Esmolol.

It is a cardioselective β 1 -blocker with a rapid onset and short duration of action. Intravenous esmolol is used for emergency control of ventricular rate in atrial flutter and atrial fibrillation. Intravenous esmolol is also highly effective for terminating an attack of PSVT. Side effects are hypotension, dizziness and bronchospasm in asthmatics.

Sotalol.

It is a nonselective β-adrenergic blocker with additional K + channel–blocking (class III) property, thus prolonging the duration of action potential. It decreases automaticity, slows AV conduction and prolongs ERP. Sotalol is used to treat life-threatening ventricular tachyarrhythmias and to maintain sinus rhythm in atrial fibrillation. Adverse effects and contraindications are same as propranolol. Sotalol can cause torsades de pointes.

Class III: Drugs that prolong duration of action potential

Amiodarone.

It is an iodine-containing compound and structurally related to thyroid hormone. It has a broad spectrum of antiarrhythmic activity.

  • ■

    Amiodarone blocks potassium channels → increases duration of action potential → prolongs refractory period and suppresses abnormal automaticity ( Fig. 3.15 ).

    Fig. 3.15
    Mechanism of action of amiodarone and other class III drugs.

  • ■

    Blocks sodium channels in the inactivated state → decreases conduction mainly in the partially depolarized tissue.

  • ■

    Blockade of sodium and potassium channels prolongs refractory period in the cardiac tissue.

  • ■

    It also has weak β-adrenergic blocking and calcium channel–blocking actions. It decreases heart rate and AV conduction.

Pharmacokinetics.

Following oral administration, bioavailability is about 30%. It can be given intravenously for rapid effect. It accumulates in fat, muscle, lungs, liver, skin, etc. and has a long half-life (1–2 months). Amiodarone is metabolized in the liver.

Uses.

Amiodarone has a broad spectrum of antiarrhythmic actions with a low incidence of torsades de pointes. It is effective in the treatment of atrial and ventricular arrhythmias. It is used to maintain normal sinus rhythm in atrial fibrillation and prevent recurrent ventricular tachycardia.

Adverse effects

  • 1.

    CVS: Hypotension (due to vasodilation), CHF and exacerbation of arrhythmias.

  • 2.

    Neurological: P eripheral neuropathy.

  • 3.

    Respiratory: P ulmonary fibrosis.

  • 4.

    GIT: Nausea and hepatitis.

  • 5.

    P hotosensitivity and p igmentation of the skin.

  • 6.

    Eye: Corneal deposits.

  • 7.

    Thyroid: Hypothyroidism and hyperthyroidism; hence TSH, T 3 and T 4 levels should be monitored during long-term therapy with amiodarone.

    • (Note the ‘Ps’.)

Drug interactions.

Amiodarone × β-blockers/verapamil: Additive depressant action on SA and AV node lead to SA block and AV block, respectively.

Amiodarone inhibits the renal clearance of digoxin, thereby increases serum digoxin levels.

It also increases concentration of quinidine and procainamide. Amiodarone potentiates the anticoagulant effect of warfarin.

Note: Amiodarone is a broad-spectrum antiarrhythmic agent with long half-life, causes multiple effects, may cause wide range of adverse effects, but does not require dose adjustment in patients with hepatic or renal disease.

Dofetilide and ibutilide are pure potassium channel blockers. They are useful in maintaining normal sinus rhythm in atrial fibrillation.

Class IV: Calcium channel blockers

Verapamil.

It blocks both activated and inactivated L-type Ca 2+ channels – depresses calcium-mediated depolarization. Verapamil decreases conduction velocity and increases refractory period of AV node; useful in

  • ■

    Terminating re-entry involving AV node (PSVT)

  • ■

    Reducing ventricular rate in atrial flutter and fibrillation

It decreases slope of phase 4 depolarization in the SA node (bradycardia) and in the ectopic foci.

Pharmacokinetics, adverse effects, drug interactions and uses are discussed on pp. 117-119.

Diltiazem.

All features are similar to verapamil but it is comparatively less potent than verapamil.

Miscellaneous agents

Adenosine.

It is a purine nucleoside that is administered as a rapid i.v. bolus for rapid control of PSVT. The duration of action of adenosine is less than 1 minute because it is rapidly transported into red blood corpuscles (RBCs) and endothelial cells.

Mechanism of action

Adenosine also decreases Ca 2+ currents in AV node → depresses AV node.

Through its action on AV node, it blocks re-entry of impulses involving AV node and terminates an attack of PSVT. It is the preferred drug for rapid termination of PSVT because it has:

  • (1)

    High efficacy.

  • (2)

    A short duration of action – adverse effects last for brief period.

  • (3)

    Minimal negative inotropic action.

Adverse effects and disadvantages.

These include A systole, B ronchospasm, C hest pain, D yspnoea, E xpensive, F lushing, H ypotension and H eadache. Side effects are transient due to its short duration of action.

Drug interactions.

Adenosine × methylxanthines: Methylxanthines antagonize the effects of adenosine by blocking its receptors.

Adenosine × dipyridamole: Dipyridamole inhibits uptake of adenosine into cells and potentiates its actions.

Magnesium.

Intravenous magnesium sulphate is useful in torsades de pointes (even if serum magnesium levels are normal). It can be used in digitalis-induced arrhythmias if there is hypomagnesaemia.

Atropine.

It is used in the treatment of bradycardia and AV block due to vagal overactivity (e.g. acute MI and digitalis toxicity). It has vagolytic action.

Isoprenaline.

Intravenous isoprenaline can be used in second degree or complete heart block following acute MI.

Some of the important drugs used in different types of cardiac arrhythmias are listed in Table 3.6 .

Table 3.6 ■
Drugs used in cardiac arrhythmias
Type of arrhythmia Drugs used
Paroxysmal supraventricular tachycardia (PSVT)
  • •

    Adenosine

  • •

    Verapamil

  • •

    Esmolol

Atrial fibrillation
  • •

    Amiodarone

  • •

    Verapamil

  • •

    Propafenone

  • •

    Digoxin

Atrial flutter
  • •

    Esmolol

  • •

    Verapamil

  • •

    Amiodarone

  • •

    Propafenone

Ventricular tachycardia
  • •

    Amiodarone

  • •

    Propranolol

Ventricular fibrillation
  • •

    Amiodarone

  • •

    Lignocaine

Hypolipidaemic drugs PH1.31

Lipoproteins are necessary for the transport of cholesterol and triglycerides in blood. The plasma lipoproteins are chylomicrons, very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). The HDL transports excess cholesterol from the peripheral tissues to liver for excretion in bile. In hyperlipoproteinaemias, the concentration of lipoproteins in plasma is elevated.

Hyperlipoproteinaemias may be primary (genetically determined) or secondary to diabetes mellitus, hypothyroidism, chronic renal disease, chronic alcoholism and drugs (β-blockers, corticosteroids, diuretics, oral contraceptives, etc.).

Classification of hypolipidaemic drugs

  • 1.

    HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins): Atorvastatin, pravastatin, pitavastatin, lovastatin, simvastatin, rosuvastatin.

  • 2.

    Fibric acid derivatives: Gemfibrozil, fenofibrate, bezafibrate, clofibrate.

  • 3.

    Bile acid–binding resins: Cholestyramine, colestipol, colesevelam.

  • 4.

    Inhibitor of triglyceride production and lipolysis: Nicotinic acid.

  • 5.

    Dietary cholesterol absorption inhibitor: Ezetimibe.

  • 6.

    Monoclonal antibodies: Alirocumab, evolocumab.

  • 7.

    Others: Gugulipid, omega-3 fatty acids.

HMG-CoA reductase inhibitors (statins)

Statins are the most effective agents for treating hyperlipidaemias. They include rosuvastatin, atorvastatin, pravastatin, pitavastatin, lovastatin and simvastatin.

Mechanism of action.

Statins competitively inhibit HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis (i.e. the conversion of HMG-CoA to mevalonate). This results in a decrease in blood LDL and VLDL levels. ↓Cholesterol synthesis →↑ LDL receptors in the liver →↑ LDL uptake and degradation. Thus, statins are very effective in reducing plasma LDL levels. They also reduce triglycerides (TGs) and increase HDL-cholesterol levels in plasma. Statins (those with short half-life) are usually given once daily in the evening because cholesterol biosynthesis occurs mainly at night. Atorvastatin and rosuvastatin have long half-life.

Among statins, lovastatin and simvastatin are prodrugs and are converted to their active forms in the liver. All statins undergo extensive first-pass metabolism in liver and most of the absorbed dose is excreted in bile. Pitavastatin is the most potent statin.

Other actions of statins – atherosclerotic plaque stability, antioxidant and antiinflammatory actions; decrease platelet aggregation; increase production of NO by endothelium. These actions also contribute to the cardioprotective effects of statins.

Adverse effects *

* Mnemonic for adverse effects of statins – HMG

  • 1.

    H epatotoxicity (dose related) with increase in serum transaminase levels.

  • 2.

    H eadache and sleep disturbances.

  • 3.

    M yopathy: Muscle pain and weakness with raised plasma creatinine kinase activity. Rhabdomyolysis may occur.

  • 4.

    G astrointestinal: Anorexia, nausea, vomiting and diarrhoea.

Statins should not be taken in pregnancy.

Uses.

Statins are the commonly used drugs for treatment of primary hyperlipidaemias with increased LDL and cholesterol levels. They are also used in secondary hyperlipidaemias due to diabetes or nephrotic syndrome.

Drug interactions.

Statins × cyclosporine/erythromycin/azoles: They inhibit the metabolism of statins (except pravastatin) → increased blood levels of statins → increased incidence of myopathy.

Bile acid–binding resins (bile acid sequestrants)

They are cholestyramine, colestipol and colesevelam.

Resins bind bile acids in the gut and interrupt their enterohepatic circulation, thus promote conversion of cholesterol to bile acids in the liver. They also stimulate the formation of hepatic LDL-receptors which take up more LDL-cholesterol from the circulation. The net effect is reduction of LDL levels with little effect on HDL level.

Uses.

Resins are used in the treatment of primary hypercholesterolaemia. Resins should be taken orally with water or fruit juice before meals. They are also useful to relieve itching of obstructive jaundice.

Adverse effects.

Since resins are not absorbed through the gut, systemic adverse effects are not seen. The common adverse effects are unpalatability, bloating, nausea, flatulence and constipation. They also bind to other drugs (thiazides, digitalis, anticoagulants, propranolol, thyroxine, fat-soluble vitamins, etc.) in the gut and reduce their absorption.

Fibrates (fibric acid derivatives)

Some of the fibrates are clofibrate, gemfibrozil, bezafibrate and fenofibrate.

They activate peroxisome proliferator-activated receptor α (PPAR-α) present in the liver, adipose tissue and skeletal muscle.

Mechanism of action

Fibrates also inhibits TG synthesis in liver. Fibrates are well absorbed after oral administration, widely distributed and concentrated in liver, kidney and intestine; metabolized in liver and excreted in urine.

Uses.

Fibrates are very effective in type III hyperlipoproteinaemia and severe hypertriglyceridaemia.

Adverse effects.

Fibrates are usually well tolerated. The common side effects are dyspepsia, nausea, vomiting, diarrhoea, muscle pain and headache. There is an increased incidence of gallstones with clofibrate. Fibrates can potentiate the effect of warfarin and oral hypoglycaemic drugs. Use of combination of gemfibrozil with statins increases the risk of myopathy. (Fenofibrate/bezafibrate can be combined with statins.) Fibrates are contraindicated in pregnancy.

Nicotinic acid (niacin)

Niacin is a B-complex vitamin. In larger doses, it has hypolipidaemic effect; it reduces plasma TGs, VLDL, LDL, and increases HDL levels. Lipoprotein(a) is decreased.

Niacin inhibits lipolysis in adipose tissue, thus reduces hepatic TG and VLDL synthesis. Niacin is the most effective agent for increasing HDL level. It should be started at a low dose and taken with meals to delay absorption. Niacin is mainly used in patients with both hypertriglyceridaemia and low HDL levels.

Adverse effects.

The main adverse effects are flushing and dyspepsia. Flushing (prostaglandin-mediated vasodilation) can be reduced either by combining niacin with aspirin or starting with a low dose of niacin. The other side effects are itching, headache, hyperpigmentation, peptic ulcer, hyperuricaemia, hepatotoxicity, hyperglycaemia and rarely atrial arrhythmias. Niacin may potentiate the effects of warfarin. It is contraindicated in pregnancy.

Ezetimibe (cholesterol absorption inhibitor)

It inhibits the absorption of dietary and biliary cholesterol in the intestine. It reduces LDL cholesterol.

Uses.

Ezetimibe is mainly used with a statin, when the LDL levels are not controlled with statin monotherapy. The combination of ezetimibe and statins has a beneficial effect. Statins inhibit cholesterol synthesis but increase intestinal cholesterol absorption. Ezetimibe inhibits intestinal cholesterol absorption but increases cholesterol synthesis. Combined use of these drugs prevents the increase in cholesterol absorption caused by statins and increased cholesterol synthesis caused by ezetimibe. The combination produces an additive reduction in LDL cholesterol levels.

Adverse effects.

There is a low incidence of hepatic dysfunction with ezetimibe.

  • Monoclonal antibodies : Alirocumab and evolocumab inhibit antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9), thus increasing hepatic clearance of LDL and lower plasma LDL levels. They are used as adjunct to statin therapy. They are administered parenterally; should be avoided in pregnancy and lactating mother.

Omega-3 fatty acids

They are effective in the treatment of hypertriglyceridaemia. They are present in fish oils. Omega-3 fatty acids activate PPAR-α and reduce triglyceride levels. Nausea and belching may occur.

Plasma volume expanders PH1.25

Plasma volume expanders are solutions used for temporary maintenance of blood volume in emergency situations. Colloidal solutions are commonly used as plasma expanders. Colloidal solutions have a high-molecular weight and exert a high oncotic pressure. The important colloidal solutions are human albumin, dextran, polyvinylpyrrolidone, hetastarch and degraded gelatin polymer.

Requirements of an ideal plasma expander

  • 1.

    The oncotic pressure, pH and viscosity of the solution should be same as that of plasma.

  • 2.

    It should be retained in the circulation for an adequate period.

  • 3.

    It should be nonpyrogenic and nonantigenic.

  • 4.

    It should be stable and cheap.

  • 5.

    It should not interfere with blood grouping and cross-matching of blood.

Human albumin

Albumin and plasma protein fraction, which are prepared from pooled human plasma are the commonly used plasma expanders. About 25 g of 5% albumin is osmotically equivalent to about 500 mL of fresh frozen plasma. This is valuable to restore colloidal osmotic pressure in hypovolaemic states, such as burns, haemorrhage and surgical procedures. There is no risk of hepatitis B/hepatitis C/HIV infections. It can cause hypersensitivity and overloading of circulation. Plasma protein fraction contains globulin in addition to albumin.

Dextran

Dextran is a water-soluble glucose polymer produced by bacteria grown on sucrose media. It is available as dextran 40 and dextran 70. Dextrans increase plasma colloidal oncotic pressure similar to that of plasma proteins.

Dextran 40.

It is given by i.v. infusion as a 10% solution. It acts rapidly but has a relatively transient effect. It reduces blood viscosity and inhibits sludging of RBCs in small blood vessels. It also improves microcirculation.

Dextran 70.

It is infused as a 6% solution and is preferred when small volumes are required. It produces less expansion of plasma volume than dextran 40. It has a longer duration of action because of its slow renal excretion. It also reduces blood viscosity and inhibits sludging of RBCs.

Dextrans may induce rouleaux formation and this interferes with blood grouping and cross-matching. They can interfere with platelet function and coagulation. The adverse effects of dextran are hypersensitivity, fever, joint pain, urticaria, hypotension, bronchospasm and rarely anaphylactic reaction. The anticoagulant effect of heparin may be enhanced by dextran.

Hydroxyethyl starch or hetastarch

It is derived from starch. It acts by increasing oncotic effect similar to that of plasma albumin. It is stable at room temperature and has a long duration of action. Hetastarch has also been used to improve granulocyte harvesting during leukapheresis procedures. It does not interfere with blood grouping and cross-matching of blood. The adverse effects are flu-like syndrome (headache, fever and myalgia), itching, urticaria and anaphylactoid reactions.

Degraded gelatin polymer

Gelatin is a polypeptide obtained from ox collagen. Gelatin in degraded form is used commonly as a plasma expander. It exerts oncotic pressure similar to that of albumin. Plasma expansion lasts for about 12 hours. It does not interfere with blood grouping and cross-matching of blood. Gelatin has also been used as a haemostatic in surgical procedures. It can cause flushing, itching, urticaria, bronchospasm and hypotension. Severe reactions can occur with urea-linked gelatin, e.g. Haemaccel.

Polyvinylpyrrolidone

This is a synthetic polymer. It interferes with blood grouping and cross-matching of blood. It binds to drugs such as insulin and penicillin in circulation and reduces their effect. It is rarely used now.

Uses of plasma expanders.

They are used to maintain circulating volume in burns, haemorrhage, severe trauma, etc. when blood/plasma is not readily available.

Contraindications.

They are severe anaemia, bleeding disorders, CHF, renal failure and hepatic failure.

Summary of selected important cardiovascular drugs
Drug Actions Cardiovascular uses Adverse effects

  • ACE inhibitors (captopril, enalapril, lisinopril, ramipril)

  • Inhibit the conversion of angiotensin I to angiotensin II resulting in:

    • •

      Dilatation of arterioles →⇩ PVR →⇩BP, ⇩afterload → ⇧CO → improve tissue perfusion

    • •

      Decrease in aldosterone production → decreases Na + , water retention → ⇩ preload

    • •

      Venodilatation →⇩ preload

    • •

      Inhibit the degradation of bradykinin

    • •

      Stimulate synthesis of vasodilating PGs

  • •

    Retard/reverse cardiac hypertrophy and remodelling

  • •

    Hypertension

  • •

    Congestive cardiac failure

  • •

    Acute myocardial infarction

  • Other uses:

    • Diabetic nephropathy

    • Scleroderma renal crisis

  • Cough, angioedema, proteinuria, teratogenic effect, hypotension (first dose phenomenon), neutropenia, rashes, itching, and loss of taste sensation

  • (Mnemonic: CAPTOPRIL)

  • Angiotensin receptor blockers (ARBs) (losartan)

  • •

    They competitively block binding of angiotensin II to AT 1 receptors on heart, peripheral vasculature and kidney

  • •

    ARBs produce effects similar to those of ACE inhibitors

  • •

    Hypertension

  • •

    Congestive cardiac failure

  • •

    Myocardial infarction

  • Other uses:

    • Diabetic nephropathy

  • Headache, hypotension, rashes, nausea, vomiting and teratogenic effects; cough and angioedema less likely than ACE inhibitors

  • Direct renin inhibitor (aliskiren)

  • By inhibiting renin, decreases levels of angiotensin I and angiotensin II

  • Hypertension

  • Headache, hypotension, diarrhoea, angioedema and abdominal pain

  • β -Adrenergic blockers

  • •

    Decrease HR, FOC, CO →⇩ BP

  • •

    Decrease renin release →⇩ BP

  • •

    Decrease sympathetic outflow from CNS →⇩ BP

  • •

    Depress SA node and AV nodal activity

  • •

    Decrease conduction in atria and AV node

  • •

    Decrease automaticity of ectopic foci

  • •

    Increase refractory period of AV node

  • •

    Decrease cardiac work, thus reduce O 2 requirement of myocardium

  • •

    Hypertension

  • •

    Prophylaxis of stable angina

  • •

    Cardiac arrhythmias (AF, AFI, PSVT)

  • •

    Myocardial infarction

  • •

    Congestive cardiac failure (metoprolol, nebivolol, carvedilol)

  • •

    Pheochromocytoma

  • •

    Hypertrophic obstructive cardiomyopathy

  • •

    Dissecting aortic aneurysm

  • Other uses:

    • •

      Glaucoma (timolol, levobunolol, betaxolol, etc.)

    • •

      Hyperthyroidism

    • •

      Prophylaxis of migraine

    • •

      Essential tremors

    • •

      Acute anxiety states

    • •

      Alcohol withdrawal

  • Bradycardia, AV block, bronchospasm, sedation, fatigue, muscular weakness, mental depression and masking of symptoms and signs of hypoglycaemia especially in diabetes patients

  • Calcium channel blockers (CCBs)

  • Dihydropyridines (nifedipine, amlodipine)

  • •

    Potent arteriolar dilators →⇩ PVR →⇩ BP, ⇩ Afterload

  • •

    Coronary vasodilatation

  • •

    Minimal direct effect on the heart

  • •

    Reflex tachycardia and palpitation are commonly seen with nifedipine; this can be minimized by using sustained release preparation or counteracted by adding a β-blocker

  • •

    Stable angina

  • •

    Variant angina

  • •

    Unstable angina

  • •

    Hypertension

  • •

    Raynaud’s phenomenon

  • •

    Subarachnoid haemorrhage (nimodipine)

  • Other uses:

    • Premature labour

  • Postural hypotension, palpitation, reflex tachycardia, ankle oedema, flushing, fatigue, sedation

  • Phenylalkylamine (verapamil)

  • •

    Has predominant action on heart than arterioles

  • •

    Decreases HR

  • •

    Decreases FOC

  • •

    Depresses SA node and slows AV conduction

  • •

    Prolongs effective refractory period

  • •

    Less potent coronary and peripheral vasodilator than DHPs

  • •

    Prophylaxis of stable angina

  • •

    Variant angina

  • •

    Unstable angina

  • •

    Hypertension

  • •

    Supraventricular arrhythmias (AF, AFI, PSVT)

  • •

    Hypertrophic cardiomyopathy

  • Other uses:

    • Prophylaxis of migraine

  • Constipation, bradycardia, AV block, oedema, may precipitate CCF in patients with low cardiac reserve

  • Benzothiazepine (diltiazem)

  • •

    Dilates peripheral and coronary arteries – less marked than nifedipine and verapamil

  • •

    Decreases force of contraction

  • •

    Decreases HR

  • •

    Depresses SA node and slows AV conduction

  • •

    Prophylaxis of stable angina

  • •

    Variant angina

  • •

    Hypertension

  • •

    Supraventricular arrhythmias (AF, AFI, PSVT)

  • Headache, hypotension, bradycardia, oedema, AV block

  • Organic nitrates

  • (Nitroglycerin, isosorbide mononitrate, isosorbide dinitrate)

  • •

    Mainly venodilators →⇩ Preload

  • •

    Arteriolar dilators →⇩ Afterload

  • •

    Dilate large coronary vessels and collateral vessels

  • •

    Have no direct action on heart

  • •

    Acute attack of angina

  • •

    Prophylaxis of angina (isosorbide mononitrate orally, isosorbide dinitrate orally, nitroglycerin-oral SR preparation/ointment/disc/patch)

  • •

    Variant angina (nitrates)

  • •

    Unstable angina (NTG: s.l./i.v.)

  • •

    Acute MI (NTG: i.v. infusion)

  • •

    Acute heart failure (i.v. NTG)

  • •

    Hypertensive emergency (i.v. NTG infusion)

  • Other uses:

    • •

      Biliary colic

    • •

      Cyanide poisoning

  • Headache, postural hypotension, reflex tachycardia, palpitation, flushing, weakness, syncope, methaemoglobinaemia, nitrate tolerance and dependence

  • Sodium nitroprusside

  • •

    Hypertensive emergencies

  • •

    Severe heart failure

  • Anorexia, nausea, vomiting, fatigue; disorientation, psychosis and convulsion (due to cyanide)

  • Potassium channel openers

  • Arteriolar dilators →⇩PVR →⇩BP

  • Hypertensive emergencies (were used)

  • Other uses:

    • Topical minoxidil – promotes hair growth in male type of baldness

  • Reflex tachycardia, Na + and water retention, headache, flushing

  • Nicorandil

  • Releases NO

  • Cardioprotective effect

  • Dilates coronary vessels and improves blood flow to myocardium

  • Angina

  • Headache, hypotension, flushing, palpitation, nausea, vomiting, ulcers in the mouth

  • Hydralazine

  • Arteriolar dilator →⇩ PVR →⇩ BP

  • Hypertension

  • Headache, hypotension, flushing, angina, MI and immunological reactions (lupus syndrome) may occur

  • α-Adrenergic blockers

  • Phenoxybenzamine

  • Nonselective, irreversible α-receptor blocker; also inhibits the reuptake of NA into the adrenergic nerve endings

  • In addition, it blocks histamine (H 1 ), cholinergic and serotonergic receptors

  • Pheochromocytoma

  • •

    Preoperatively

  • •

    Inoperable cases

  • Postural hypotension, tachycardia, palpitation, diarrhoea, nasal stuffiness, giddiness, impotence

  • Phentolamine

  • Nonselective, reversible α-blocker; has rapid onset but short duration of action on i.v. administration

  • •

    i.v. Phentolamine is used:

    • •

      To control hypertensive crisis due to clonidine withdrawal, cheese reaction

    • •

      To control hypertensive episodes intraoperatively during surgery of pheochromocytoma

  • •

    Local infiltration to prevent tissue necrosis due to extravasation of α agonists.

  • Tachycardia, palpitation, arrhythmias, angina and MI

  • Prazosin

  • Selective α 1 -receptor blockers

  • Hypertension

  • Terazosin

  • Arteriolar and venodilators; arteriolar dilatation is more marked

  • Benign prostatic hyperplasia (BPH)

  • First dose postural hypotension, nasal congestion, tachycardia, impaired ejaculation, impotence

  • Doxazosin

  • Tamsulosin

  • Uroselective α 1 (α 1A ) receptor blocker

  • Benign prostatic hyperplasia (BPH)

  • Retrograde ejaculation, postural hypotension

  • Phosphodiesterase 5 inhibitors (PDE-5)

  • Sildenafil

  • Vardenafil

  • Tadalafil

  • •

    Pulmonary hypertension (sildenafil)

  • •

    Erectile dysfunction

  • Headache, flushing, hypotension, colour vision defects and diarrhoea

  • Adenosine

  • i.v. adenosine, acts rapidly, depresses SA node, atrial and AV nodal conduction

  • To terminate an attack of PSVT

  • A systole, B ronchospasm, C hest pain, D yspnoea, E xpensive, F lushing, hypotension, headache

  • Amiodarone

  • Has broad spectrum of antiarrhythmic activity

  • •

    Blocks potassium channels

  • •

    Blocks Na + channel in inactivated state

  • •

    Has β-adrenergic blocking action

  • •

    Has calcium channel–blocking action

  • Ventricular and supraventricular arrhythmias

  • Hypotension, peripheral neuropathy, pulmonary fibrosis, nausea, hepatitis, photosensitivity, corneal deposits, hypothyroidism and hyperthyroidism

  • Lignocaine

  • •

    Class IB antiarrhythmic drug

  • •

    Blocks Na + channels in the inactivated (predominantly) and the active states

  • •

    Decreases automaticity of ectopic foci

  • •

    Depresses conduction in depolarized tissue

  • •

    Action potential duration is usually unaffected or may be shortened

  • •

    Ventricular arrhythmias associated with MI, digitalis toxicity and cardiac surgery

  • •

    As local anaesthetic

  • Headache, drowsiness, nystagmus, blurred vision, confusion, convulsion

  • Digoxin

  • •

    Has direct and indirect actions on the heart

  • •

    Direct action by inhibiting Na + K + -ATPase

  • •

    Indirect action by stimulating vagus (vagomimetic effect)

  • •

    Has positive inotropic effect

  • •

    Decreases heart rate by direct and indirect actions

  • •

    At therapeutic concentration, decreases automaticity, prolongs ERP and decreases conduction velocity in AV node

  • •

    At higher concentration, increases automaticity in cardiac tissue by direct action as well as by increasing sympathetic activity

  • •

    CCF (low output failure)

  • •

    Atrial fibrillation

  • •

    Atrial flutter

  • •

    PSVT

  • •

    Cardiac: Digitalis can cause any type of arrhythmias

  • •

    Ventricular premature beats, pulsus bigeminy, ventricular tachycardia, AV block, atrial tachycardia, atrial fibrillation, atrial flutter, severe bradycardia, anorexia, nausea, vomiting, headache, confusion, restlessness, disorientation, weakness, visual disturbance

  • Endothelin (ET) receptor antagonists

  • Bosentan, macitentan (block ET A and ET B receptors); Ambresantan (blocks ET A receptors)

  • Vasodilation mainly pulmonary, coronary, renal blood vessels

  • Pulmonary arterial hypertension

  • Increase in hepatic aminotransferases, headache, flushing due to vasodilation

  • Pentoxiphylline

  • Decreases viscosity of blood, improves microcirculation

  • Peripheral vascular disease

  • Nausea, vomiting

  • Cilostazol

  • Inhibits PDE 3, causes vasodilation and inhibits platelet aggregation

  • Peripheral vascular disease

  • Nausea, vomiting, headache